BRS Physiology, 5th Edition (Board Review Series)

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Author: Linda S. Costanzo

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98761_FM 10/05/10 8:28 PM Page i

Physiology

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Physiology Linda S. Costanzo, Ph.D. Professor of Physiology and Biophysics Medical College of Virginia Virginia Commonwealth University Richmond, Virginia

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Acquisitions Editor: Crystal Taylor Product Manager: Stacey L. Sebring Designer: Holly Reid McLaughlin Compositor: MPS Limited, A Macmillan Company

Copyright © 2011 Lippincott Williams & Wilkins Two Commerce Square 2001 Market Street Philadelphia, PA 19103

All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner. The publisher is not responsible (as a matter of product liability, negligence, or otherwise) for any injury resulting from any material contained herein. This publication contains information relating to general principles of medical care that should not be construed as specific instructions for individual patients. Manufacturers’ product information and package inserts should be reviewed for current information, including contraindications, dosages, and precautions. Printed in China First Edition, 1995 Second Edition, 1998 Third Edition, 2003 Fourth Edition, 2007 Library of Congress Cataloging-in-Publication Data Costanzo, Linda S., 1947Physiology/Linda S. Costanzo. —5th ed. p. ; cm. —(Board review series) Includes bibliographical references and index. ISBN 978-0-7817-9876-1 (alk. paper) 1. Human physiology—Examinations, questions, etc. I. Title. II. Series: Board review series. [DNLM: 1. Physiological Phenomena—Examination Questions. 2. Physiology—Examination Questions. QT 18.2 C838p 2011] QP40.C67 2011 612’.0076—dc22 2010018984 The publishers have made every effort to trace the copyright holders for borrowed material. If they have inadvertently overlooked any, they will be pleased to make the necessary arrangements at the first opportunity. To purchase additional copies of this book, call our customer service department at (800) 638-3030 or fax orders to (301) 223-2320. International customers should call (301) 223-2300. Visit Lippincott Williams & Wilkins on the Internet: http://www.LWW.com. Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to 6:00 pm, EST. 1 2 3 4 5 6 7 8 9 10

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For Richard And for Dan and Rebecca

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Preface

The subject matter of physiology is the foundation of the practice of medicine, and a firm grasp of its principles is essential for the physician. This book is intended to aid the student preparing for the United States Medical Licensing Examination (USMLE) Step 1. It is a concise review of key physiologic principles and is intended to help the student recall material taught during the first and second years of medical school. It is not intended to substitute for comprehensive textbooks or for course syllabi, although the student may find it a useful adjunct to physiology and pathophysiology courses. The material is organized by organ system into seven chapters. The first chapter reviews general principles of cellular physiology. The remaining six chapters review the major organ systems—neurophysiology, cardiovascular, respiratory, renal and acid–base, gastrointestinal, and endocrine physiology. Difficult concepts are explained stepwise, concisely, and clearly, with appropriate illustrative examples and sample problems. Numerous clinical correlations are included so that the student can understand physiology in relation to medicine. An integrative approach is used, when possible, to demonstrate how the organ systems work together to maintain homeostasis. More than 130 full-color illustrations and flow diagrams and more than 50 tables help the student visualize the material quickly and aid in long-term retention. The inside front cover contains “Key Physiology Topics for USMLE Step 1.” The inside back cover contains “Key Physiology Equations for USMLE Step 1.” Questions reflecting the content and format of USMLE Step 1 are included at the end of each chapter and in a Comprehensive Examination at the end of the book. These questions, many with clinical relevance, require problem-solving skills rather than straight recall. Clear, concise explanations accompany the questions and guide the student through the correct steps of reasoning. The questions can be used as a pretest to identify areas of weakness or as a post test to determine mastery. Special attention should be given to the Comprehensive Examination, because its questions integrate several areas of physiology and related concepts of pathophysiology and pharmacology. New to this edition: ■ ■ ■ ■

Addition of new full-color figures Updated organization and text Expanded coverage of cellular, respiratory, renal, gastrointestinal, and endocrine physiology Increased emphasis on pathophysiology

Best of luck in your preparation for USMLE Step 1! Linda S. Costanzo, Ph.D. Chapter 3

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Acknowledgments

It has been a pleasure to be a part of the Board Review Series and to work with the staff at Lippincott Williams & Wilkins. Crystal Taylor and Stacey Sebring provided expert editorial assistance. Matthew Chansky again served as illustrator, revising and colorizing existing figures and creating new ones. My sincere thanks to students in the School of Medicine at Virginia Commonwealth University/Medical College of Virginia, who have provided so many helpful suggestions for BRS Physiology. Thanks also to the many students from other medical schools who have taken the time to write to me about their experiences with this book. Linda S. Costanzo, Ph.D.

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Contents

Preface vii Acknowledgments ix

1.

CELL PHYSIOLOGY I. II. III. IV. V. VI. VII. VIII.

1

Cell Membranes 1 Transport Across Cell Membranes 2 Osmosis 5 Diffusion Potential, Resting Membrane Potential, and Action Potential 7 Neuromuscular and Synaptic Transmission 12 Skeletal Muscle 16 Smooth Muscle 20 Comparison of Skeletal Muscle, Smooth Muscle, and Cardiac Muscle 22

Review Test 23

2.

NEUROPHYSIOLOGY

31

I. Autonomic Nervous System

II. III. IV. V. VI.

31 Sensory Systems 35 Motor Systems 47 Higher Functions of the Cerebral Cortex 53 Blood–Brain Barrier and Cerebrospinal Fluid 54 Temperature Regulation 55

Review Test 57

3.

CARDIOVASCULAR PHYSIOLOGY

64

I. Circuitry of the Cardiovascular System 64 II. Hemodynamics 64 III. Cardiac Electrophysiology 69 IV. Cardiac Muscle and Cardiac Output 74 Chapter

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Contents

V. VI. VII. VIII. IX.

Cardiac Cycle 83 Regulation of Arterial Pressure 85 Microcirculation and Lymph 89 Special Circulations 92 Integrative Functions of the Cardiovascular System: Gravity, Exercise, and Hemorrhage 95

Review Test 100

4.

RESPIRATORY PHYSIOLOGY

113

I. Lung Volumes and Capacities

II. III. IV. V. VI. VII. VIII. IX.

113 Mechanics of Breathing 115 Gas Exchange 122 Oxygen Transport 123 CO2 Transport 128 Pulmonary Circulation 129 V/Q Defects 131 Control of Breathing 132 Integrated Responses of the Respiratory System 134

Review Test 136

5.

RENAL AND ACID–BASE PHYSIOLOGY

144

I. Body Fluids

II. III. IV. V. VI. VII. VIII. IX. X. XI.

144 Renal Clearance, Renal Blood Flow, and Glomerular Filtration Rate 148 Reabsorption and Secretion 152 NaCl Regulation 155 K⫹ Regulation 159 Renal Regulation of Urea, Phosphate, Calcium, and Magnesium 162 Concentration and Dilution of Urine 163 Renal Hormones 168 Acid–Base Balance 168 Diuretics 177 Integrative Examples 177

Review Test 180

6.

GASTROINTESTINAL PHYSIOLOGY I. Structure and Innervation of the Gastrointestinal Tract

II. III. IV. V. VI.

190 Regulatory Substances in the Gastrointestinal Tract 191 Gastrointestinal Motility 195 Gastrointestinal Secretion 199 Digestion and Absorption 209 Liver Physiology 214

Review Test 216

190

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Contents

7.

ENDOCRINE PHYSIOLOGY I. Overview of Hormones

222 Cell Mechanisms and Second Messengers 224 Pituitary Gland (Hypophysis) 227 Thyroid Gland 232 Adrenal Cortex and Adrenal Medulla 235 Endocrine Pancreas—Glucagon and Insulin 242 Calcium Metabolism (Parathyroid Hormone, Vitamin D, Calcitonin) 245 VIII. Sexual Differentiation 249 IX. Male Reproduction 250 X. Female Reproduction 253 II. III. IV. V. VI. VII.

Review Test 257

Comprehensive Examination 265 Index 287

xiii

222

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chapter

1

Cell Physiology

I. CELL MEMBRANES ■

are composed primarily of phospholipids and proteins.

A. Lipid bilayer 1. Phospholipids have a glycerol backbone, which is the hydrophilic (water-soluble) head, and two fatty acid tails, which are hydrophobic (water-insoluble). The hydrophobic tails face each other and form a bilayer.

2. Lipid-soluble substances (e.g., O2, CO2, steroid hormones) cross cell membranes because they can dissolve in the hydrophobic lipid bilayer.

3. Water-soluble substances (e.g., Na+, Cl–, glucose, H2O) cannot dissolve in the lipid of the membrane, but may cross through water-filled channels, or pores, or may be transported by carriers.

B. Proteins 1. Integral proteins ■ ■ ■

are anchored to, and imbedded in, the cell membrane through hydrophobic interactions. may span the cell membrane. include ion channels, transport proteins, receptors, and guanosine 5′-triphosphate (GTP)-binding proteins (G proteins).

2. Peripheral proteins ■ ■ ■

are not imbedded in the cell membrane. are not covalently bound to membrane components. are loosely attached to the cell membrane by electrostatic interactions.

C. Intercellular connections 1. Tight junctions (zonula occludens) ■ ■ ■

are the attachments between cells (often epithelial cells). may be an intercellular pathway for solutes, depending on the size, charge, and characteristics of the tight junction. may be “tight” (impermeable), as in the renal distal tubule, or “leaky” (permeable), as in the renal proximal tubule and gallbladder.

2. Gap junctions ■ ■

are the attachments between cells that permit intercellular communication. for example, permit current flow and electrical coupling between myocardial cells.

1

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2

Board Review Series: Physiology t a b l e

1-1

Characteristics of Different Types of Transport

Type

Electrochemical Gradient

CarrierMediated

Metabolic Energy

Na+ Gradient

Inhibition of Na+–K+ Pump

Simple diffusion Facilitated diffusion Primary active transport

Downhill Downhill Uphill

No Yes Yes

No No Yes

No No —

Cotransport Countertransport

Uphill* Uphill*

Yes Yes

Indirect Indirect

Yes, same direction Yes, opposite direction

— — Inhibits (if Na+– K+ pump) Inhibits Inhibits

*One or more solutes are transported uphill; Na+ is transported downhill.

II. TRANSPORT ACROSS CELL MEMBRANES (TABLE 1.1) A. Simple diffusion 1. Characteristics of simple diffusion ■ ■ ■

is the only form of transport that is not carrier-mediated. occurs down an electrochemical gradient (“downhill”). does not require metabolic energy and therefore is passive.

2. Diffusion can be measured using the following equation: J ⴝ ⴚPA (C1 ⴚ C2 ) where: J = flux (flow) (mmol/sec) P = permeability (cm/sec) A = area (cm2) C1 = concentration1 (mmol/L) C2 = concentration2 (mmol/L)

3. Sample calculation for diffusion ■

The urea concentration of blood is 10 mg/100 mL. The urea concentration of proximal tubular fluid is 20 mg/100 mL. If the permeability to urea is 1 × 10–5 cm/ sec and the surface area is 100 cm2, what are the magnitude and direction of the urea flux?

⎛ 1 × 10−5 cm ⎞ 10 mg ⎞ 2 ⎛ 20 mg Flux = ⎜ − ⎟ (100 cm ) ⎜ ⎟ sec ⎝ 100 mL 100 mL ⎠ ⎝ ⎠ ⎛ 1 × 10−5 cm ⎞ 2 ⎛ 10 mg ⎞ =⎜ ⎟ (100 cm ) ⎜ ⎟ sec ⎝ 100 mL ⎠ ⎝ ⎠ ⎛ 1 × 10−5 cm ⎞ 2 ⎛ 0.1 mg ⎞ =⎜ ⎟ (100 cm ) ⎜ 3 ⎟ sec ⎝ cm ⎠ ⎝ ⎠ en to blood (high to low concentration) = 1 × 10−4 mg/sec from lume

Note: The minus sign preceding the diffusion equation indicates that the direction of flux, or flow, is from high to low concentration. It can be ignored if the higher concentration is called C1 and the lower concentration is called C2. Also note: 1 mL = 1 cm3.

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Chapter 1 Cell Physiology

3

4. Permeability ■ ■ ■

is the P in the equation for diffusion. describes the ease with which a solute diffuses through a membrane. depends on the characteristics of the solute and the membrane.

a. Factors that increase permeability: ■ ■ ■

↑ Oil/water partition coefficient of the solute increases solubility in the lipid of the membrane. ↓ Radius (size) of the solute increases the diffusion coefficient and speed of diffusion. ↓ Membrane thickness decreases the diffusion distance.

b. Small hydrophobic solutes (e.g., O2) have the highest permeabilities in lipid membranes. c. Hydrophilic solutes (e.g., Na+) must cross cell membranes through water-filled channels, or pores. If the solute is an ion (is charged), then its flux will depend on both the concentration difference and the potential difference across the membrane.

B. Carrier-mediated transport ■ ■

includes facilitated diffusion and primary and secondary active transport. The characteristics of carrier-mediated transport are:

1. Stereospecificity. For example, D-glucose (the natural isomer) is transported by facilitated diffusion, but the L-isomer is not. Simple diffusion, in contrast, would not distinguish between the two isomers because it does not involve a carrier. 2. Saturation. The transport rate increases as the concentration of the solute increases, until the carriers are saturated. The transport maximum (Tm) is analogous to the maximum velocity (Vmax) in enzyme kinetics. 3. Competition. Structurally related solutes compete for transport sites on carrier molecules. For example, galactose is a competitive inhibitor of glucose transport in the small intestine.

C. Facilitated diffusion 1. Characteristics of facilitated diffusion ■ ■ ■ ■

occurs down an electrochemical gradient (“downhill”), similar to simple diffusion. does not require metabolic energy and therefore is passive. is more rapid than simple diffusion. is carrier-mediated and therefore exhibits stereospecificity, saturation, and competition.

2. Example of facilitated diffusion ■

Glucose transport in muscle and adipose cells is “downhill,” is carrier-mediated, and is inhibited by sugars such as galactose; therefore, it is categorized as facilitated diffusion. In diabetes mellitus, glucose uptake by muscle and adipose cells is impaired because the carriers for facilitated diffusion of glucose require insulin.

D. Primary active transport 1. Characteristics of primary active transport ■ ■ ■

occurs against an electrochemical gradient (“uphill”). requires direct input of metabolic energy in the form of adenosine triphosphate (ATP) and therefore is active. is carrier-mediated and therefore exhibits stereospecificity, saturation, and competition.

2. Examples of primary active transport a. Na+,K+-ATPase (or Na+–K+ pump) in cell membranes transports Na+ from intracellular to extracellular fluid and K+ from extracellular to intracellular fluid; it maintains low intracellular [Na+] and high intracellular [K+].

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4

Board Review Series: Physiology ■ ■ ■ ■

Both Na+ and K+ are transported against their electrochemical gradients. Energy is provided from the terminal phosphate bond of ATP. The usual stoichiometry is 3 Na+/2 K+. Specific inhibitors of Na+,K+-ATPase are the cardiac glycoside drugs ouabain and digitalis.

b. Ca2+-ATPase (or Ca2+ pump) in the sarcoplasmic reticulum (SR) or cell membranes transports Ca2+ against an electrochemical gradient. ■

Sarcoplasmic and endoplasmic reticulum Ca2+-ATPase is called SERCA.

c. H+,K+-ATPase (or proton pump) in gastric parietal cells transports H+ into the lumen of the stomach against its electrochemical gradient. ■

It is inhibited by proton pump inhibitors, such as omeprazole.

E. Secondary active transport 1. Characteristics of secondary active transport a. The transport of two or more solutes is coupled. b. One of the solutes (usually Na+) is transported “downhill” and provides energy for the “uphill” transport of the other solute(s).

c. Metabolic energy is not provided directly, but indirectly from the Na+ gradient that is maintained across cell membranes. Thus, inhibition of Na+,K+-ATPase will decrease transport of Na+ out of the cell, decrease the transmembrane Na+ gradient, and eventually inhibit secondary active transport. d. If the solutes move in the same direction across the cell membrane, it is called cotransport, or symport. ■

Examples are Na+–glucose cotransport in the small intestine and Na+–K+–2Cl– cotransport in the renal thick ascending limb.

e. If the solutes move in opposite directions across the cell membranes, it is called countertransport, exchange, or antiport. ■

Examples are Na+–Ca2+ exchange and Na+–H+ exchange.

2. Example of Na+–glucose cotransport (Figure 1-1) a. The carrier for Na+–glucose cotransport is located in the luminal membrane of intestinal mucosal and renal proximal tubule cells.

b. Glucose is transported “uphill”; Na+ is transported “downhill.” c. Energy is derived from the “downhill” movement of Na+. The inwardly directed Na+ gradient is maintained by the Na+–K+ pump on the basolateral (blood side) membrane. Poisoning the Na+–K+ pump decreases the transmembrane Na+ gradient and consequently inhibits Na+–glucose cotransport.

Lumen

Intestinal or proximal tubule cell

Na+

Na+ Glucose

Blood

Na+ K+

Na+

Na+ Secondary active

Primary active

FIGURE 1-1 Na+–glucose cotransport (symport) in intestinal or proximal tubule epithelial cell.

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5

Chapter 1 Cell Physiology Secondary active Na+

Ca2+ Na+

Ca2+

Ca2+

Na+

Na+

K+

FIGURE 1-2 Na+–Ca+ countertransport (antiport).

Primary active

3. Example of Na+–Ca2+ countertransport or exchange (Figure 1-2) a. Many cell membranes contain a Na+–Ca2+ exchanger that transports Ca2+ “uphill” from low intracellular [Ca2+] to high extracellular [Ca2+]. Ca2+ and Na+ move in opposite directions across the cell membrane. b. The energy is derived from the “downhill” movement of Na+. As with cotransport, the inwardly directed Na+ gradient is maintained by the Na+–K+ pump. Poisoning the Na+–K+ pump therefore inhibits Na+–Ca2+ exchange.

III. OSMOSIS A. Osmolarity ■ ■ ■

is the concentration of osmotically active particles in a solution. is a colligative property that can be measured by freezing point depression. can be calculated using the following equation: Osmolarity ⴝ g ⴛ C where: Osmolarity = concentration of particles (osm/L) g = number of particles in solution (osm/mol) [e.g., gNaCl = 2; gglucose = 1] C = concentration (mol/L)

■

■

Two solutions that have the same calculated osmolarity are isosmotic. If two solutions have different calculated osmolarities, the solution with the higher osmolarity is hyperosmotic and the solution with the lower osmolarity is hyposmotic. Sample calculation: What is the osmolarity of a 1 M NaCl solution? Osmolarity = g × C = 2 osm mol × 1 M = 2 osm L

B. Osmosis and osmotic pressure ■

Osmosis is the flow of water across a semipermeable membrane from a solution with low solute concentration to a solution with high solute concentration.

1. Example of osmosis (Figure 1-3) a. Solutions 1 and 2 are separated by a semipermeable membrane. Solution 1 contains a solute that is too large to cross the membrane. Solution 2 is pure water. The presence of the solute in solution 1 produces an osmotic pressure.

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6

Board Review Series: Physiology Semipermeable membrane

Time Water flows by osmosis from 2 1 1

2

1

2

FIGURE 1-3 Osmosis of H2O across a semipermeable membrane.

b. The osmotic pressure difference across the membrane causes water to flow from solution 2 (which has no solute and the lower osmotic pressure) to solution 1 (which has the solute and the higher osmotic pressure). c. With time, the volume of solution 1 increases and the volume of solution 2 decreases.

2. Calculating osmotic pressure (van’t Hoff’s law) a. The osmotic pressure of solution 1 (see Figure 1-3) can be calculated by van’t Hoff’s law, which states that osmotic pressure depends on the concentration of osmotically active particles. The concentration of particles is converted to pressure according to the following equation: o ⴝ g ⴛ C ⴛ RT where: π = osmotic pressure (mm Hg or atm) g = number of particles in solution (osm/mol) C = concentration (mol/L) R = gas constant (0.082 L—atm/mol—K) T = absolute temperature (K)

b. The osmotic pressure increases when the solute concentration increases. A solution of 1 M CaCl2 has a higher osmotic pressure than a solution of 1 M KCl because the concentration of particles is higher. c. The higher the osmotic pressure of a solution, the greater the water flow into it. d. Two solutions having the same effective osmotic pressure are isotonic because no water flows across a semipermeable membrane separating them. If two solutions separated by a semipermeable membrane have different effective osmotic pressures, the solution with the higher effective osmotic pressure is hypertonic and the solution with the lower effective osmotic pressure is hypotonic. Water flows from the hypotonic to the hypertonic solution. e. Colloidosmotic pressure, or oncotic pressure, is the osmotic pressure created by proteins (e.g., plasma proteins).

3. Reflection coefficient (σ) ■

is a number between zero and one that describes the ease with which a solute permeates a membrane.

a. If the reflection coefficient is one, the solute is impermeable. Therefore, it is retained in the original solution, it creates an osmotic pressure, and it causes water flow. Serum albumin (a large solute) has a reflection coefficient of nearly one. b. If the reflection coefficient is zero, the solute is completely permeable. Therefore, it will not exert any osmotic effect, and it will not cause water flow. Urea (a small solute) has a reflection coefficient of close to zero and it is, therefore, an ineffective osmole. 4. Calculating effective osmotic pressure ■

Effective osmotic pressure is the osmotic pressure (calculated by van’t Hoff’s law) multiplied by the reflection coefficient.

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Chapter 1 Cell Physiology ■

7

If the reflection coefficient is one, the solute will exert maximal effective osmotic pressure. If the reflection coefficient is zero, the solute will exert no osmotic pressure.

IV. DIFFUSION POTENTIAL, RESTING MEMBRANE POTENTIAL, AND ACTION POTENTIAL A. Ion channels ■

are integral proteins that span the membrane and, when open, permit the passage of certain ions.

1. Ion channels are selective; they permit the passage of some ions, but not others. Selectivity is based on the size of the channel and the distribution of charges that line it. ■

For example, a small channel lined with negatively charged groups will be selective for small cations and exclude large solutes and anions. Conversely, a small channel lined with positively charged groups will be selective for small anions and exclude large solutes and cations.

2. Ion channels may be open or closed. When the channel is open, the ion(s) for which it is selective can flow through. When the channel is closed, ions cannot flow through.

3. The conductance of a channel depends on the probability that the channel is open. The higher the probability that a channel is open, the higher the conductance, or permeability. Opening and closing of channels are controlled by gates. a. Voltage-gated channels are opened or closed by changes in membrane potential. ■

■

The activation gate of the Na+ channel in nerve is opened by depolarization; when open, the nerve membrane is permeable to Na+ (e.g., during the upstroke of the nerve action potential). The inactivation gate of the Na+ channel in nerve is closed by depolarization; when closed, the nerve membrane is impermeable to Na+ (e.g., during the repolarization phase of the nerve action potential).

b. Ligand-gated channels are opened or closed by hormones, second messengers, or neurotransmitters. ■

For example, the nicotinic receptor for acetylcholine (ACh) at the motor end plate is an ion channel that opens when ACh binds to it. When open, it is permeable to Na+ and K+, causing the motor end plate to depolarize.

B. Diffusion and equilibrium potentials ■ ■ ■ ■ ■ ■

A diffusion potential is the potential difference generated across a membrane because of a concentration difference of an ion. A diffusion potential can be generated only if the membrane is permeable to the ion. The size of the diffusion potential depends on the size of the concentration gradient. The sign of the diffusion potential depends on whether the diffusing ion is positively or negatively charged. Diffusion potentials are created by the diffusion of very few ions and, therefore, do not result in changes in concentration of the diffusing ions. The equilibrium potential is the diffusion potential that exactly balances (opposes) the tendency for diffusion caused by a concentration difference. At electrochemical equilibrium, the chemical and electrical driving forces that act on an ion are equal and opposite, and no more net diffusion of the ion occurs.

1. Example of a Na+ diffusion potential (Figure 1-4) a. Two solutions of NaCl are separated by a membrane that is permeable to Na+ but not to Cl–. The NaCl concentration of solution 1 is higher than that of solution 2.

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8

Board Review Series: Physiology Na+-selective membrane 1

2

1

Na+

Na+ Na+

Cl–

2

Cl–

Cl–

– – – –

+ + + +

Na+

Cl–

FIGURE 1-4 Generation of a Na+ diffusion potential across a Na+-selective membrane.

b. Because the membrane is permeable to Na+, Na+ will diffuse from solution 1 to solution 2 down its concentration gradient. Cl– is impermeable and therefore will not accompany Na+. c. As a result, a diffusion potential will develop and solution 1 will become negative with respect to solution 2. d. Eventually, the potential difference will become large enough to oppose further net diffusion of Na+. The potential difference that exactly counterbalances the diffusion of Na+ down its concentration gradient is the Na+ equilibrium potential. At electrochemical equilibrium, the chemical and electrical driving forces on Na+ are equal and opposite, and there is no net diffusion of Na+. 2. Example of a Cl– diffusion potential (Figure 1-5) a. Two solutions identical to those shown in Figure 1-4 are now separated by a membrane that is permeable to Cl– rather than to Na+. b. Cl– will diffuse from solution 1 to solution 2 down its concentration gradient. Na+ is impermeable and therefore will not accompany Cl–. c. A diffusion potential will be established such that solution 1 will become positive with respect to solution 2. The potential difference that exactly counterbalances the diffusion of Cl– down its concentration gradient is the Cl– equilibrium potential. At electrochemical equilibrium, the chemical and electrical driving forces on Cl– are equal and opposite, and there is no net diffusion of Cl–.

3. Using the Nernst equation to calculate equilibrium potentials a. The Nernst equation is used to calculate the equilibrium potential at a given concentration difference of a permeable ion across a cell membrane. It tells us what potential would exactly balance the tendency for diffusion down the concentration gradient; in other words, at what potential would the ion be at electrochemical

equilibrium? E ⴝ ⴚ2.3

RT [ Ci ] log10 zF [ Ce ]

Cl–-selective membrane 1

2

Na+

1

Na+ Na+

Cl–

Cl–

Cl–

FIGURE 1-5 Generation of a Cl– diffusion potential across a Cl– -selective membrane.

2

+ + + +

– – – –

Na+

Cl–

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9

where: E = equilibrium potential (mV)

2 .3

RT = 60 mV at 37ºC zF z = charge on the ion (+1 for Na+; +2 for Ca2+; –1 for Cl–) Ci = intracellular concentration (mM) Ce = extracellular concentration (mM)

b. Sample calculation with the Nernst equation ■

If the intracellular [Na+] is 15 mM and the extracellular [Na+] is 150 mM, what is the equilibrium potential for Na+? ENa =

−60 mV log10 z

=

−60 mV log10 +1

+

⎡⎣Ci ⎤⎦ ⎡⎣Ce ⎤⎦ 15 mM 150 mM

= −60 mV log10 0.1 = +60 mV Note: You need not remember which concentration goes in the numerator. Because it is a log function, perform the calculation either way to get the absolute value of 60 mV. Then use an “intuitive approach” to determine the correct sign. (Intuitive approach: The [Na+] is higher in extracellular fluid than in intracellular fluid, so Na+ ions will diffuse from extracellular to intracellular, making the inside of the cell positive [i.e., +60 mV at equilibrium].)

c. Approximate values for equilibrium potentials in nerve and muscle ENa+ ECa2+ EK+ ECl–

+65 mV +120 mV –85 mV –85 mV

C. Resting membrane potential ■ ■

is expressed as the measured potential difference across the cell membrane in millivolts (mV). is, by convention, expressed as the intracellular potential relative to the extracellular potential. Thus, a resting membrane potential of –70 mV means 70 mV, cell negative.

1. The resting membrane potential is established by diffusion potentials that result from concentration differences of permeant ions.

2. Each permeable ion attempts to drive the membrane potential toward its equilibrium potential. Ions with the highest permeabilities, or conductances, will make the greatest contributions to the resting membrane potential, and those with the lowest permeabilities will make little or no contribution. 3. For example, the resting membrane potential of nerve is –70 mV, which is close to the calculated K+ equilibrium potential of –85 mV, but far from the calculated Na+ equilibrium potential of +65 mV. At rest, the nerve membrane is far more permeable to K+ than to Na+. 4. The Na+–K+ pump contributes only indirectly to the resting membrane potential by maintaining, across the cell membrane, the Na+ and K+ concentration gradients that then produce diffusion potentials. The direct electrogenic contribution of the pump (3 Na+ pumped out of the cell for every 2 K+ pumped into the cell) is small.

D. Action potentials 1. Definitions a. Depolarization makes the membrane potential less negative (the cell interior becomes less negative).

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Board Review Series: Physiology

Absolute refractory period

Relative refractory period Na+ equilibrium potential

Voltage or conductance

+65 mV Action potential

0 mV

Na+ conductance

K+ conductance –70 mV

Resting membrane potential

–85 mV

K+ equilibrium potential 2.0

1.0 Time

(msec) FIGURE 1-6 Nerve action potential and associated changes in Na+ and K+ conductance.

b. Hyperpolarization makes the membrane potential more negative (the cell interior becomes more negative).

c. Inward current is the flow of positive charge into the cell. Inward current depolarizes the membrane potential.

d. Outward current is the flow of positive charge out of the cell. Outward current hyperpolarizes the membrane potential. e. Action potential is a property of excitable cells (i.e., nerve, muscle) that consists of a rapid depolarization, or upstroke, followed by repolarization of the membrane potential. Action potentials have stereotypical size and shape, are propagating, and are all-or-none. f. Threshold is the membrane potential at which the action potential is inevitable. At threshold potential, net inward current becomes larger than net outward current. The resulting depolarization becomes self-sustaining and gives rise to the upstroke of the action potential. If net inward current is less than net outward current, no action potential will occur (i.e., all-or-none response). 2. Ionic basis of the nerve action potential (Figure 1-6)

a. Resting membrane potential ■ ■ ■

is approximately –70 mV, cell negative. is the result of the high resting conductance to K+, which drives the membrane potential toward the K+ equilibrium potential. At rest, the Na+ channels are closed and Na+ conductance is low.

b. Upstroke of the action potential (1) Inward current depolarizes the membrane potential to threshold. (2) Depolarization causes rapid opening of the activation gates of the Na+ channel, and the Na+ conductance of the membrane promptly increases. (3) The Na+ conductance becomes higher than the K+ conductance, and the membrane potential is driven toward (but does not quite reach) the Na+ equilibrium potential of +65 mV. Thus, the rapid depolarization during the upstroke is caused by an inward Na+ current.

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11

(4) The overshoot is the brief portion at the peak of the action potential when the membrane potential is positive. (5) Tetrodotoxin (TTX) and lidocaine block these voltage-sensitive Na+ channels and abolish action potentials.

c. Repolarization of the action potential (1) Depolarization also closes the inactivation gates of the Na+ channel (but more slowly than it opens the activation gates). Closure of the inactivation gates results in closure of the Na+ channels, and the Na+ conductance returns toward zero. (2) Depolarization slowly opens K+ channels and increases K+ conductance to even higher levels than at rest. (3) The combined effect of closing the Na+ channels and greater opening of the K+ channels makes the K+ conductance higher than the Na+ conductance, and the membrane potential is repolarized. Thus, repolarization is caused by an outward K+ current.

d. Undershoot (hyperpolarizing afterpotential) ■

The K+ conductance remains higher than at rest for some time after closure of the Na+ channels. During this period, the membrane potential is driven very close to the K+ equilibrium potential.

3. Refractory periods (see Figure 1-6) a. Absolute refractory period ■ ■ ■

is the period during which another action potential cannot be elicited, no matter how large the stimulus. coincides with almost the entire duration of the action potential. Explanation: Recall that the inactivation gates of the Na+ channel are closed when the membrane potential is depolarized. They remain closed until repolarization occurs. No action potential can occur until the inactivation gates open.

b. Relative refractory period ■ ■ ■

begins at the end of the absolute refractory period and continues until the membrane potential returns to the resting level. An action potential can be elicited during this period only if a larger than usual inward current is provided. Explanation: The K+ conductance is higher than at rest, and the membrane potential is closer to the K+ equilibrium potential and, therefore, farther from threshold; more inward current is required to bring the membrane to threshold.

c. Accommodation ■ ■ ■

occurs when the cell membrane is held at a depolarized level such that the threshold potential is passed without firing an action potential. occurs because depolarization closes inactivation gates on the Na+ channels. is demonstrated in hyperkalemia, in which skeletal muscle membranes are depolarized by the high serum K+ concentration. Although the membrane potential is closer to threshold, action potentials do not occur because inactivation gates on Na+ channels are closed by depolarization, causing muscle weakness.

4. Propagation of action potentials (Figure 1-7) ■ ■

occurs by the spread of local currents to adjacent areas of membrane, which are then depolarized to threshold and generate action potentials. Conduction velocity is increased by:

a. ↑ fiber size. Increasing the diameter of a nerve fiber results in decreased internal resistance; thus, conduction velocity down the nerve is faster.

b. Myelination. Myelin acts as an insulator around nerve axons and increases conduction velocity. Myelinated nerves exhibit saltatory conduction because action potentials can be generated only at the nodes of Ranvier, where there are gaps in the myelin sheath (Figure 1-8).

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12


+ –

+ –

+ –

+ –

– +

+ –

+ –

+ –

+ –

FIGURE 1-7 Unmyelinated axon showing spread of depolarization by local current flow. Box shows active zone where action potential has reversed the polarity.

Myelin sheath

Node of Ranvier FIGURE 1-8 Myelinated axon. Action potentials can occur at nodes of Ranvier.

V. NEUROMUSCULAR AND SYNAPTIC TRANSMISSION A. General characteristics of chemical synapses 1. An action potential in the presynaptic cell causes depolarization of the presynaptic terminal. 2. As a result of the depolarization, Ca2+ enters the presynaptic terminal, causing release of neurotransmitter into the synaptic cleft. 3. Neurotransmitter diffuses across the synaptic cleft and combines with receptors on the postsynaptic cell membrane, causing a change in its permeability to ions and, consequently, a change in its membrane potential.

4. Inhibitory neurotransmitters hyperpolarize the postsynaptic membrane; excitatory neurotransmitters depolarize the postsynaptic membrane. B. Neuromuscular junction (Figure 1-9 and Table 1.2) ■ ■

is the synapse between axons of motoneurons and skeletal muscle. The neurotransmitter released from the presynaptic terminal is ACh, and the postsynaptic membrane contains a nicotinic receptor.

1. Synthesis and storage of ACh in the presynaptic terminal ■ ■

Choline acetyltransferase catalyzes the formation of ACh from acetyl coenzyme A (CoA) and choline in the presynaptic terminal. ACh is stored in synaptic vesicles with ATP and proteoglycan for later release.

AChR Action potential in nerve 1

3

ACh

Action potential in muscle 5 K+

Na+ Ca2+ 2

4

Motoneuron FIGURE 1-9 Neuromuscular junction. ACh = acetylcholine; AChR = acetylcholine receptor.

Muscle

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Chapter 1 Cell Physiology t a b l e

1-2

Agents Affecting Neuromuscular Transmission

Example

Action

Effect on Neuromuscular Transmission

Botulinus toxin

Blocks release of ACh from presynaptic terminals Competes with ACh for receptors on motor end plate Inhibits acetylcholinesterase

Total blockade

Curare Neostigmine Hemicholinium

13

Blocks reuptake of choline into presynaptic terminal

Decreases size of EPP; maximal doses produce paralysis of respiratory muscles and death Prolongs and enhances action of ACh at muscle end plate Depletes ACh stores from presynaptic terminal

ACh = acetylcholine; EPP = end plate potential.

2. Depolarization of the presynaptic terminal and Ca2+ uptake ■ ■

Action potentials are conducted down the motoneuron. Depolarization of the presynaptic terminal opens Ca2+ channels. When Ca2+ permeability increases, Ca2+ rushes into the presynaptic terminal down its electrochemical gradient.

3. Ca2+ uptake causes release of ACh into the synaptic cleft ■

The synaptic vesicles fuse with the plasma membrane and empty their contents into the cleft by exocytosis.

4. Diffusion of ACh to the postsynaptic membrane (muscle end plate) and binding of ACh to nicotinic receptors ■ ■

The nicotinic ACh receptor is also a Na+ and K+ ion channel. Binding of ACh to α subunits of the receptor causes a conformational change that opens the central core of the channel and increases its conductance to Na+ and K+. These are examples of ligand-gated channels.

5. End plate potential (EPP) in the postsynaptic membrane ■

■ ■

Because the channels opened by ACh conduct both Na+ and K+ ions, the postsynaptic membrane potential is depolarized to a value halfway between the Na+ and K+ equilibrium potentials (approximately 0 mV). The contents of one synaptic vesicle (one quantum) produce a miniature end plate potential (MEPP), the smallest possible EPP. MEPPs summate to produce a full-fledged EPP. The EPP is not an action potential, but simply a depolarization of the specialized muscle end plate.

6. Depolarization of adjacent muscle membrane to threshold ■

Once the end plate region is depolarized, local currents cause depolarization and action potentials in the adjacent muscle tissue. Action potentials in the muscle are followed by contraction.

7. Degradation of Ach ■ ■ ■ ■

The EPP is transient because ACh is degraded to acetyl CoA and choline by acetylcholinesterase (AChE) on the muscle end plate. One-half of the choline is taken back into the presynaptic ending by Na+–choline cotransport and used to synthesize new ACh. AChE inhibitors (neostigmine) block the degradation of ACh, prolong its action at the muscle end plate, and increase the size of the EPP. Hemicholinium blocks choline reuptake and depletes the presynaptic endings of ACh stores.

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8. Disease—myasthenia gravis ■ ■ ■ ■

is caused by the presence of antibodies to the ACh receptor. is characterized by skeletal muscle weakness and fatigability resulting from a reduced number of ACh receptors on the muscle end plate. The size of the EPP is reduced; therefore, it is more difficult to depolarize the muscle membrane to threshold and to produce action potentials. Treatment with AChE inhibitors (e.g., neostigmine) prevents the degradation of ACh and prolongs the action of ACh at the muscle end plate, partially compensating for the reduced number of receptors.

C. Synaptic transmission 1. Types of arrangements a. One-to-one synapses (such as those found at the neuromuscular junction) ■

An action potential in the presynaptic element (the motor nerve) produces an action potential in the postsynaptic element (the muscle).

b. Many-to-one synapses (such as those found on spinal motoneurons) ■

An action potential in a single presynaptic cell is insufficient to produce an action potential in the postsynaptic cell. Instead, many cells synapse on the postsynaptic cell to depolarize it to threshold. The presynaptic input may be excitatory or inhibitory.

2. Input to synapses ■ ■

The postsynaptic cell integrates excitatory and inhibitory inputs. When the sum of the input brings the membrane potential of the postsynaptic cell to threshold, it fires an action potential.

a. Excitatory postsynaptic potentials (EPSPs) ■ ■

■

are inputs that depolarize the postsynaptic cell, bringing it closer to threshold and closer to firing an action potential. are caused by opening of channels that are permeable to Na+ and K+, similar to the ACh channels. The membrane potential depolarizes to a value halfway between the equilibrium potentials for Na+ and K+ (approximately 0 mV). Excitatory neurotransmitters include ACh, norepinephrine, epinephrine, dopamine, glutamate, and serotonin.

b. Inhibitory postsynaptic potentials (IPSPs) ■ ■ ■

are inputs that hyperpolarize the postsynaptic cell, moving it away from threshold and farther from firing an action potential. are caused by opening Cl– channels. The membrane potential is hyperpolarized toward the Cl– equilibrium potential (–90 mV). Inhibitory neurotransmitters are γ-aminobutyric acid (GABA) and glycine.

3. Summation at synapses a. Spatial summation occurs when two excitatory inputs arrive at a postsynaptic neuron simultaneously. Together, they produce greater depolarization.

b. Temporal summation occurs when two excitatory inputs arrive at a postsynaptic neuron in rapid succession. Because the resulting postsynaptic depolarizations overlap in time, they add in stepwise fashion. c. Facilitation, augmentation, and post-tetanic potentiation occur after tetanic stimulation of the presynaptic neuron. In each of these, depolarization of the postsynaptic neuron is greater than expected because greater than normal amounts of neurotransmitter are released, possibly because of the accumulation of Ca2+ in the presynaptic terminal. ■

Long-term potentiation (memory) involves new protein synthesis.

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15

Tyrosine tyrosine hydroxylase L-dopa dopa decarboxylase

Dopamine dopamine β-hydroxylase

Norepinephrine phenylethanolamine-N-methyltransferase (S-adenosylmethionine)

Epinephrine FIGURE 1-10 Synthetic pathway for dopamine, norepinephrine, and epinephrine.

4. Neurotransmitters a. ACh (see V B) b. Norepinephrine, epinephrine, and dopamine (Figure 1-10) (1) Norepinephrine ■ ■ ■

is the primary transmitter released from postganglionic sympathetic neurons. is synthesized in the nerve terminal and released into the synapse to bind with ` or a receptors on the postsynaptic membrane. is removed from the synapse by reuptake or is metabolized in the presynaptic terminal by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). The metabolites are:

(a) (b) (c) (d) ■

3,4-Dihydroxymandelic acid (DOMA) Normetanephrine (NMN) 3-Methoxy-4-hydroxyphenylglycol (MOPEG) 3-Methoxy-4-hydroxymandelic acid, or vanillylmandelic acid (VMA)

In pheochromocytoma, a tumor of the adrenal medulla that secretes catecholamines, urinary excretion of VMA is increased.

(2) Epinephrine ■ ■

is synthesized from norepinephrine by the action of phenylethanolamine-Nmethyltransferase. is secreted, along with norepinephrine, from the adrenal medulla.

(3) Dopamine ■ ■ ■

is prominent in midbrain neurons. is released from the hypothalamus and inhibits prolactin secretion; in this context it is called prolactin-inhibiting factor (PIF). is metabolized by MAO and COMT.

(a) D1 receptors activate adenylate cyclase via a Gs protein. (b) D2 receptors inhibit adenylate cyclase via a Gi protein. (c) Parkinson’s disease involves degeneration of dopaminergic neurons that use the D2 receptors.

(d) Schizophrenia involves increased levels of D2 receptors.

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c. Serotonin ■ ■ ■

is present in high concentrations in the brain stem. is formed from tryptophan. is converted to melatonin in the pineal gland.

d. Histamine ■ ■

is formed from histidine. is present in the neurons of the hypothalamus.

e. Glutamate ■ ■ ■ ■

is the most prevalent excitatory neurotransmitter in the brain. There are four subtypes of glutamate receptors. Three subtypes are ionotropic receptors (ligand-gated ion channels) including the NMDA (N-methyl-D-aspartate) receptor. One subtype is a metabotropic receptor, which is coupled to ion channels via a heterotrimeric G protein.

f. GABA ■ ■ ■

is an inhibitory neurotransmitter. is synthesized from glutamate by glutamate decarboxylase. has two types of receptors:

(1) The GABAA receptor increases Cl– conductance and is the site of action of benzodiazepines and barbiturates.

(2) The GABAB receptor increases K+ conductance. g. Glycine ■ ■

is an inhibitory neurotransmitter found primarily in the spinal cord and brain stem. increases Cl– conductance.

h. Nitric oxide (NO) ■ ■ ■ ■

is a short-acting inhibitory neurotransmitter in the gastrointestinal tract, blood vessels, and the central nervous system. is synthesized in presynaptic nerve terminals, where NO synthase converts arginine to citrulline and NO. is a permeant gas that diffuses from the presynaptic terminal to its target cell. also functions in signal transduction of guanylyl cyclase in a variety of tissues, including vascular smooth muscle.

VI. SKELETAL MUSCLE A. Muscle structure and filaments (Figure 1-11) ■ ■ ■

Each muscle fiber is multinucleate and behaves as a single unit. It contains bundles of myofibrils, surrounded by SR and invaginated by transverse tubules (T tubules). Each myofibril contains interdigitating thick and thin filaments arranged longitudinally in sarcomeres. Repeating units of sarcomeres account for the unique banding pattern in striated muscle. A sarcomere runs from Z line to Z line.

1. Thick filaments ■ ■

are present in the A band in the center of the sarcomere. contain myosin.

98761_Ch01 5/7/10 6:38 PM Page 17


A

Motoneuron

Sarcomere

17

Muscle I band

I band Thin filament

Thick filament

Myofibril

Z line

M line

Z line

H band A band

B

Transverse tubules Sarcolemmal membrane

Terminal cisternae

Sarcoplasmic reticulum

FIGURE 1-11 Structure of the sarcomere in skeletal muscle. A. Arrangement of thick and thin filaments. B. Transverse tubules and sarcoplasmic reticulum.

a. Myosin has six polypeptide chains, including one pair of heavy chains and two pairs of light chains. b. Each myosin molecule has two “heads” attached to a single “tail.” The myosin heads bind ATP and actin, and are involved in cross-bridge formation.

2. Thin filaments ■ ■ ■ ■

are anchored at the Z lines. are present in the I bands. interdigitate with the thick filaments in a portion of the A band. contain actin, tropomyosin, and troponin.

a. Troponin is the regulatory protein that permits cross-bridge formation when it binds Ca2+.

b. Troponin is a complex of three globular proteins: ■ ■ ■

Troponin T (“T” for tropomyosin) attaches the troponin complex to tropomyosin. Troponin I (“I” for inhibition) inhibits the interaction of actin and myosin. Troponin C (“C” for Ca2+) is the Ca2+-binding protein that, when bound to Ca2+, permits the interaction of actin and myosin.

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18


3. T tubules ■ ■ ■

are an extensive tubular network, open to the extracellular space, that carry the depolarization from the sarcolemmal membrane to the cell interior. are located at the junctions of A bands and I bands. contain a voltage-sensitive protein called the dihydropyridine receptor; depolarization causes a conformational change in the dihydropyridine receptor.

4. SR ■ ■ ■ ■ ■

is the internal tubular structure that is the site of Ca2+ storage and release for excitation–contraction coupling. has terminal cisternae that make intimate contact with the T tubules in a triad arrangement. membrane contains Ca2+-ATPase (Ca2+ pump), which transports Ca2+ from intracellular fluid into the SR interior, keeping intracellular [Ca2+] low. contains Ca2+ bound loosely to calsequestrin. contains a Ca2+ release channel called the ryanodine receptor.

B. Steps in excitation–contraction coupling in skeletal muscle (Figures 1-12 and 1-13) 1. Action potentials in the muscle cell membrane initiate depolarization of the T tubules. 2. Depolarization of the T tubules causes a conformational change in its dihydropyridine receptor, which opens Ca2+ release channels (ryanodine receptors) in the nearby SR, causing release of Ca2+ from the SR into the intracellular fluid.

3. Intracellular [Ca2+] increases.

Actin filament +

– Myosin head

Myosin filament

A +

–

+

–

ATP

ADP

D

B +

–

ADP Pi

C FIGURE 1-12 Cross-bridge cycle. Myosin “walks” toward the plus end of actin to produce shortening and forcegeneration. ADP = adenosine diphosphate; ATP = adenosine triphosphate; Pi = inorganic phosphate.

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19

Action potential

Response

Intracellular [Ca2+]

FIGURE 1-13 Relationship of the action potential, the increase in intracellular [Ca2+], and muscle contraction in skeletal muscle.

Twitch tension

Time

4. Ca2+ binds to troponin C on the thin filaments, causing a conformational change in troponin that moves tropomyosin out of the way. The cross-bridge cycle begins (see Figure 1-12):

a. At first, no ATP is bound to myosin (A), and myosin is tightly attached to actin. In rapidly contracting muscle, this stage is brief. In the absence of ATP, this state is permanent (i.e., rigor). b. ATP then binds to myosin (B), producing a conformational change in myosin that causes myosin to be released from actin. c. Myosin is displaced toward the plus end of actin. There is hydrolysis of ATP to ADP and inorganic phosphate (Pi). ADP remains attached to myosin (C). d. Myosin attaches to a new site on actin, which constitutes the power (force-generating) stroke (D). ADP is then released, returning myosin to its rigor state. e. The cycle repeats as long as Ca2+ is bound to troponin C. Each cross-bridge cycle “walks” myosin further along the actin filament. 5. Relaxation occurs when Ca2+ is reaccumulated by the SR Ca2+-ATPase (SERCA). Intracellular Ca2+ concentration decreases, Ca2+ is released from troponin C, and tropomyosin again blocks the myosin-binding site on actin. As long as intracellular Ca2+ concentration is low, cross-bridge cycling cannot occur. 6. Mechanism of tetanus. A single action potential causes the release of a standard amount of Ca2+ from the SR and produces a single twitch. However, if the muscle is stimulated repeatedly, more Ca2+ is released from the SR and there is a cumulative increase in intracellular [Ca2+], extending the time for cross-bridge cycling. The muscle does not relax (tetanus).

C. Length–tension and force–velocity relationships in muscle ■

■

Isometric contractions are measured when length is held constant. Muscle length (preload) is fixed, the muscle is stimulated to contract, and the developed tension is measured. There is no shortening. Isotonic contractions are measured when load is held constant. The load against which the muscle contracts (afterload) is fixed, the muscle is stimulated to contract, and shortening is measured.

1. Length–tension relationship (Figure 1-14) ■

measures tension developed during isometric contractions when the muscle is set to fixed lengths (preload).

a. Passive tension is the tension developed by stretching the muscle to different lengths. b. Total tension is the tension developed when the muscle is stimulated to contract at different lengths.

c. Active tension is the difference between total tension and passive tension.

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Tension

Total

Passive Length at maximum cross-bridge overlap

Active

Muscle length FIGURE 1-14 Length–tension relationship in skeletal muscle.

■ ■

Active tension represents the active force developed from contraction of the muscle. It can be explained by the cross-bridge cycle model. Active tension is proportional to the number of cross-bridges formed. Tension will be maximum when there is maximum overlap of thick and thin filaments. When the muscle is stretched to greater lengths, the number of cross-bridges is reduced because there is less overlap. When muscle length is decreased, the thin filaments collide and tension is reduced.

2. Force–velocity relationship (Figure 1-15) ■ ■

measures the velocity of shortening of isotonic contractions when the muscle is challenged with different afterloads (the load against which the muscle must contract). The velocity of shortening decreases as the afterload increases.

VII. SMOOTH MUSCLE ■

has thick and thin filaments that are not arranged in sarcomeres; therefore, they appear homogeneous rather than striated.

A. Types of smooth muscle 1. Multi-unit smooth muscle ■

is present in the iris, ciliary muscle of the lens, and vas deferens. behaves as separate motor units.

Initial velocity of shortening

■

Afterload FIGURE 1-15 Force–velocity relationship in skeletal muscle.

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Chapter 1 Cell Physiology ■ ■

21

has little or no electrical coupling between cells. is densely innervated; contraction is controlled by neural innervation (e.g., autonomic nervous system).

2. Unitary (single-unit) smooth muscle ■ ■ ■

is the most common type and is present in the uterus, gastrointestinal tract, ureter, and bladder. is spontaneously active (exhibits slow waves) and exhibits “pacemaker” activity (see Chapter 6 III A), which is modulated by hormones and neurotransmitters. has a high degree of electrical coupling between cells and, therefore, permits coordinated contraction of the organ (e.g., bladder).

3. Vascular smooth muscle ■

has properties of both multi-unit and single-unit smooth muscle.

B. Steps in excitation–contraction coupling in smooth muscle (Figure 1-16) ■

The mechanism of excitation–contraction coupling is different from that in skeletal muscle.

Hormones or neurotransmitters Depolarization

Opens voltage-gated Ca2+ channels

IP3

Hormones or neurotransmitters

Ca2+ release from SR

Open ligand-gated Ca2+ channels

[Ca2+]

Ca2+-calmodulin (CaM)

myosin-light-chain kinase

Phosphorylation of myosin light chains

Myosin ATPase

Myosin~P + actin

Cross-bridge cycling

FIGURE 1-16 Sequence of events in contraction of smooth muscle.

Tension

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Board Review Series: Physiology ■

There is no troponin; instead, Ca2+ regulates myosin on the thick filaments.

1. Depolarization of the cell membrane opens voltage-gated Ca2+ channels and Ca2+ flows into the cell down its electrochemical gradient, increasing the intracellular [Ca2+]. Hormones and neurotransmitters may open ligand-gated Ca2+ channels in the cell membrane. They also directly release Ca2+ from the SR through inositol 1,4,5-triphosphate

(IP3)-gated Ca2+ channels. 2. Intracellular [Ca2+] increases. 3. Ca2+ binds to calmodulin. The Ca2+–calmodulin complex binds to and activates myosin light-chain kinase. When activated, myosin light-chain kinase phosphorylates myosin and allows it to bind to actin, thus initiating cross-bridge cycling. The amount of tension produced is proportional to the intracellular Ca2+ concentration. 4. A decrease in intracellular [Ca2+] produces relaxation.

VIII. COMPARISON OF SKELETAL MUSCLE, SMOOTH MUSCLE, AND CARDIAC MUSCLE ■ ■

Table 1-3 compares the ionic basis for the action potential and mechanism of contraction in skeletal muscle, smooth muscle, and cardiac muscle. Cardiac muscle is discussed in Chapter 3.

t a b l e

1-3

Comparison of Skeletal, Smooth, and Cardiac Muscle

Feature

Skeletal Muscle

Smooth Muscle

Cardiac Muscle

Appearance Upstroke of action potential

Striated Inward Na+ current

No striations Inward Ca2+ current

Plateau

No

No

Duration of action potential

~1 msec

~10 msec

Excitation–contraction coupling

Action potential → T tubules

Action potential opens voltage-gated Ca2+ channels in cell membrane

Striated Inward Ca2+ current (SA node) Inward Na+ current (atria, ventricles, Purkinje fibers) No (SA node) Yes (atria, ventricles, Purkinje fibers; due to inward Ca2+ current) 150 msec (SA node, atria) 250–300 msec (ventricles and Purkinje fibers) Inward Ca2+ current during plateau of action potential

Ca2+ released from nearby SR ↑ [Ca2+]i

Molecular basis for contraction

Ca2+–troponin C

Ca2+-induced Ca2+ release from SR Hormones and transmitters open IP3 – gated Ca2+ channels in SR

↑ [Ca2+]i

Ca2+–calmodulin ↑ myosin light-chain kinase

Ca2+–troponin C

IP3 = inositol 1,4,5-triphosphate; SA = sinoatrial; SR = sarcoplasmic reticulum.

98761_Ch01 5/7/10 6:38 PM Page 23

Review Test 1. Which of the following characteristics is shared by simple and facilitated diffusion of glucose? (A) (B) (C) (D) (E)

Occurs down an electrochemical gradient Is saturable Requires metabolic energy Is inhibited by the presence of galactose Requires a Na+ gradient

(B)

(C)

(D) 2. During the upstroke of the nerve action potential (A) there is net outward current and the cell

(E)

interior becomes more negative

(B) there is net outward current and the cell interior becomes less negative

(C) there is net inward current and the cell interior becomes more negative

(D) there is net inward current and the cell

5. Which characteristic or component is shared by skeletal muscle and smooth muscle? (A) Thick and thin filaments arranged in sarcomeres

interior becomes less negative

3. Solutions A and B are separated by a semipermeable membrane that is permeable to K+, but not to Cl–. Solution A is 100 mM KCl, and solution B is 1 mM KCl. Which of the following statements about solution A and solution B is true? (A) K+ ions will diffuse from solution A to

(B)

(C)

(D)

(E)

solution B until the [K+ ] of both solutions is 50.5 mM K+ ions will diffuse from solution B to solution A until the [K+ ] of both solutions is 50.5 mM KCl will diffuse from solution A to solution B until the [KCl] of both solutions is 50.5 mM K+ will diffuse from solution A to solution B until a membrane potential develops with solution A negative with respect to solution B K+ will diffuse from solution A to solution B until a membrane potential develops with solution A positive with respect to solution B

4. The correct temporal sequence for events at the neuromuscular junction is (A) action potential in the motor nerve; depolarization of the muscle end plate;

uptake of Ca2+ into the presynaptic nerve terminal uptake of Ca2+ into the presynaptic terminal; release of acetylcholine (ACh); depolarization of the muscle end plate release of ACh; action potential in the motor nerve; action potential in the muscle uptake of Ca2+ into the motor end plate; action potential in the motor end plate; action potential in the muscle release of ACh; action potential in the muscle end plate; action potential in the muscle

(B) Troponin (C) Elevation of intracellular [Ca2+] for excitation–contraction coupling

(D) Spontaneous depolarization of the membrane potential

(E) High degree of electrical coupling between cells

6. Repeated stimulation of a skeletal muscle fiber causes a sustained contraction (tetanus). Accumulation of which solute in intracellular fluid is responsible for the tetanus?

(A) (B) (C) (D) (E) (F) (G) (H)

Na+ K+ Cl– Mg2+ Ca2+ Troponin Calmodulin Adenosine triphosphate (ATP)

7. Solutions A and B are separated by a membrane that is permeable to Ca2+ and impermeable to Cl–. Solution A contains 10 mM CaCl2, and solution B contains 1 mM CaCl2. Assuming that 2.3 RT/F = 60 mV, Ca2+ will be at electrochemical equilibrium when (A) solution A is +60 mV (B) solution A is +30 mV

23

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24


(C) (D) (E) (F) (G)

solution A is –60 mV solution A is –30 mV solution A is +120 mV solution A is –120 mV the Ca2+ concentrations of the two solutions are equal (H) the Cl– concentrations of the two solutions are equal

8. A 42-year-old man with myasthenia gravis notes increased muscle strength when he is treated with an acetylcholinesterase (AChE) inhibitor. The basis for his improvement is increased (A) amount of acetylcholine (ACh) released from motor nerves

(B) levels of ACh at the muscle end plates (C) number of ACh receptors on the muscle end plates (D) amount of norepinephrine released from motor nerves (E) synthesis of norepinephrine in motor nerves

11. Solutions A and B are separated by a membrane that is permeable to urea. Solution A is 10 mM urea, and solution B is 5 mM urea. If the concentration of urea in solution A is doubled, the flux of urea across the membrane will

(A) (B) (C) (D) (E)

double triple be unchanged decrease to one-half decrease to one-third

12. A muscle cell has an intracellular [Na+] of 14 mM and an extracellular [Na+ ] of 140 mM. Assuming that 2.3 RT/F = 60 mV, what would the membrane potential be if the muscle cell membrane were permeable only to Na+?

(A) (B) (C) (D) (E)

80 mV –60 mV 0 mV +60 mV +80 mV

Questions 13–15 is infused with large volumes of a solution that causes lysis of her red blood cells (RBCs). The solution was most likely

(A) (B) (C) (D) (E)

150 mM NaCl 300 mM mannitol 350 mM mannitol 300 mM urea 150 mM CaCl2

10. During a nerve action potential, a stimulus is delivered as indicated by the arrow shown in the following figure. In response to the stimulus, a second action potential

The following diagram of a nerve action potential applies to Questions 13–15. Na+ equilibrium potential 3

+35 mV

Membrane potential

9. In a hospital error, a 60-year-old woman

0 mV 2 4

–70 mV

1 5

K+ equilibrium potential

1.0 2.0 Time (msec)

Stimulus

13. At which labeled point on the action potential is the K+ closest to electrochemical equilibrium?

(A) (B) (C) (D) (E)

1 2 3 4 5

(A) of smaller magnitude will occur (B) of normal magnitude will occur (C) of normal magnitude will occur, but will

14. What process is responsible for the

be delayed (D) will occur, but will not have an overshoot (E) will not occur

(A) Movement of Na+ into the cell (B) Movement of Na+ out of the cell (C) Movement of K+ into the cell

change in membrane potential that occurs between point 1 and point 3?

98761_Ch01 5/7/10 6:38 PM Page 25


(D) Movement of K+ out of the cell (E) Activation of the Na+–K+ pump (F) Inhibition of the Na+–K+ pump

(B) Doubling the oil/water partition coefficient of the solute

(C) Doubling the thickness of the bilayer (D) Doubling the concentration difference of the solute across the bilayer

15. What process is responsible for the change in membrane potential that occurs between point 3 and point 4?

(A) (B) (C) (D) (E) (F)

Movement of Na+ into the cell Movement of Na+ out of the cell Movement of K+ into the cell Movement of K+ out of the cell Activation of the Na+–K+ pump Inhibition of the Na+–K+ pump

16. The velocity of conduction of action potentials along a nerve will be increased by

(A) (B) (C) (D) (E)

stimulating the Na+–K+ pump inhibiting the Na+–K+ pump decreasing the diameter of the nerve myelinating the nerve lengthening the nerve fiber

17. Solutions A and B are separated by a semipermeable membrane. Solution A contains 1 mM sucrose and 1 mM urea. Solution B contains 1 mM sucrose. The reflection coefficient for sucrose is one and the reflection coefficient for urea is zero. Which of the following statements about these solutions is correct? (A) Solution A has a higher effective osmotic pressure than solution B

25

20. A newly developed local anesthetic blocks Na+ channels in nerves. Which of the following effects on the action potential would it be expected to produce?

(A) Decrease the rate of rise of the upstroke of the action potential

(B) Shorten the absolute refractory period (C) Abolish the hyperpolarizing afterpotential

(D) Increase the Na+ equilibrium potential (E) Decrease the Na+ equilibrium potential 21. At the muscle end plate, acetylcholine (ACh) causes the opening of

(A) Na+ channels and depolarization toward the Na+ equilibrium potential

(B) K+ channels and depolarization toward the K+ equilibrium potential (C) Ca2+ channels and depolarization toward the Ca2+ equilibrium potential (D) Na+ and K+ channels and depolarization to a value halfway between the Na+ and K+ equilibrium potentials (E) Na+ and K+ channels and hyperpolarization to a value halfway between the Na+ and K+ equilibrium potentials

(B) Solution A has a lower effective osmotic pressure than solution B

(C) Solutions A and B are isosmotic (D) Solution A is hyperosmotic with respect to solution B, and the solutions are isotonic (E) Solution A is hyposmotic with respect to solution B, and the solutions are isotonic

18. Transport of D- and L-glucose proceeds at the same rate down an electrochemical gradient by which of the following processes? (A) (B) (C) (D) (E)

Simple diffusion Facilitated diffusion Primary active transport Cotransport Countertransport

22. An inhibitory postsynaptic potential (A) depolarizes the postsynaptic membrane by opening Na+ channels (B) depolarizes the postsynaptic membrane by opening K+ channels (C) hyperpolarizes the postsynaptic membrane by opening Ca2+ channels (D) hyperpolarizes the postsynaptic membrane by opening Cl– channels

23. Which of the following would occur as a result of the inhibition of Na+,K+-ATPase?

(A) (B) (C) (D) (E)

Decreased intracellular Na+ concentration Increased intracellular K+ concentration Increased intracellular Ca2+ concentration Increased Na+–glucose cotransport Increased Na+–Ca2+ exchange

19. Which of the following will double the permeability of a solute in a lipid bilayer?

24. Which of the following temporal

(A) Doubling the molecular radius of the

sequences is correct for excitation– contraction coupling in skeletal muscle?

solute

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26


(A) Increased intracellular [Ca2+]; action potential in the muscle membrane; cross-bridge formation (B) Action potential in the muscle membrane; depolarization of the T tubules; release of Ca2+ from the sarcoplasmic reticulum (SR) (C) Action potential in the muscle membrane; splitting of adenosine triphosphate (ATP); binding of Ca2+ to troponin C (D) Release of Ca2+ from the SR; depolarization of the T tubules; binding of Ca2+ to troponin C

(E) Absorption of glucose by intestinal epithelial cells

29. Which of the following causes rigor in skeletal muscle?

(A) (B) (C) (D)

No action potentials in motoneurons An increase in intracellular Ca2+ level A decrease in intracellular Ca2+ level An increase in adenosine triphosphate (ATP) level (E) A decrease in ATP level

30. Degeneration of dopaminergic neurons

25. Which of the following transport process-

has been implicated in

es is involved if transport of glucose from the intestinal lumen into a small intestinal cell is inhibited by abolishing the usual Na+ gradient across the cell membrane?

(A) (B) (C) (D)

(A) (B) (C) (D) (E)


26. In skeletal muscle, which of the following events occurs before depolarization of the T tubules in the mechanism of excitation– contraction coupling?

(A) Depolarization of the sarcolemmal (B) (C) (D) (E)

membrane Opening of Ca2+ release channels on the sarcoplasmic reticulum (SR) Uptake of Ca2+ into the SR by Ca2+-adenosine triphosphatase (ATPase) Binding of Ca2+ to troponin C Binding of actin and myosin

27. Which of the following is an inhibitory neurotransmitter in the central nervous system (CNS)?

(A) (B) (C) (D) (E)

Norepinephrine Glutamate γ -Aminobutyric acid (GABA) Serotonin Histamine

28. Adenosine triphosphate (ATP) is used indirectly for which of the following processes?

31. Assuming complete dissociation of all solutes, which of the following solutions would be hyperosmotic to 1 mM NaCl?

(A) (B) (C) (D) (E)

1 mM glucose 1.5 mM glucose 1 mM CaCl2 1 mM sucrose 1 mM KCl

32. A new drug is developed that blocks the transporter for H+ secretion in gastric parietal cells. Which of the following transport processes is being inhibited?

(A) (B) (C) (D) (E)


33. A 56-year-old woman with severe muscle weakness is hospitalized. The only abnormality in her laboratory values is an elevated serum K+ concentration. The elevated serum K+ causes muscle weakness because (A) the resting membrane potential is hyperpolarized

(B) the K+ equilibrium potential is

(A) Accumulation of Ca2+ by the sarcoplasmic reticulum (SR) (B) Transport of Na+ from intracellular to extracellular fluid (C) Transport of K+ from extracellular to intracellular fluid (D) Transport of H+ from parietal cells into the lumen of the stomach

schizophrenia Parkinson’s disease myasthenia gravis curare poisoning

hyperpolarized

(C) the Na+ equilibrium potential is (D) (E) (F) (G)

hyperpolarized K+ channels are closed by depolarization K+ channels are opened by depolarization Na+ channels are closed by depolarization Na+ channels are opened by depolarization

98761_Ch01 5/7/10 6:38 PM Page 27

Answers and Explanations 1. The answer is A [II A 1, C]. Both types of transport occur down an electrochemical gradient (“downhill”), and do not require metabolic energy. Saturability and inhibition by other sugars are characteristic only of carrier-mediated glucose transport; thus, facilitated diffusion is saturable and inhibited by galactose, whereas simple diffusion is not.

2. The answer is D [IV D 1 a, b, 2 b]. During the upstroke of the action potential, the cell depolarizes, or becomes less negative. The depolarization is caused by inward current, which is, by definition, the movement of positive charge into the cell. In nerve and in most types of muscle, this inward current is carried by Na+.

3. The answer is D [IV B]. Because the membrane is permeable only to K+ ions, K+ will diffuse down its concentration gradient from solution A to solution B, leaving some Cl– ions behind in solution A. A diffusion potential will be created, with solution A negative with respect to solution B. Generation of a diffusion potential involves movement of only a few ions and, therefore, does not cause a change in the concentration of the bulk solutions.

4. The answer is B [V B 1–6]. Acetylcholine (ACh) is stored in vesicles and is released when an action potential in the motor nerve opens Ca2+ channels in the presynaptic terminal. ACh diffuses across the synaptic cleft and opens Na+ and K+ channels in the muscle end plate, depolarizing it (but not producing an action potential). Depolarization of the muscle end plate causes local currents in adjacent muscle membrane, depolarizing the membrane to threshold and producing action potentials.

5. The answer is C [VI A, B 1–4; VII B 1–4]. An elevation of intracellular [Ca2+] is common to the mechanism of excitation–contraction coupling in skeletal and smooth muscle. In skeletal muscle, Ca2+ binds to troponin C, initiating the cross-bridge cycle. In smooth muscle, Ca2+ binds to calmodulin. The Ca2+–calmodulin complex activates myosin lightchain kinase, which phosphorylates myosin so that shortening can occur. The striated appearance of the sarcomeres and the presence of troponin are characteristic of skeletal, not smooth, muscle. Spontaneous depolarizations and gap junctions are characteristics of unitary smooth muscle but not skeletal muscle.

6. The answer is E [VI B 6]. During repeated stimulation of a muscle fiber, Ca2+ is released from the sarcoplasmic reticulum (SR) more quickly than it can be reaccumulated; therefore, the intracellular [Ca2+] does not return to resting levels as it would after a single twitch. The increased [Ca2+] allows more cross-bridges to form and, therefore, produces increased tension (tetanus). Intracellular Na+ and K+ concentrations do not change during the action potential. Very few Na+ or K+ ions move into or out of the muscle cell, so bulk concentrations are unaffected. Adenosine triphosphate (ATP) levels would, if anything, decrease during tetanus.

7. The answer is D [IV B]. The membrane is permeable to Ca2+, but impermeable to Cl–. Although there is a concentration gradient across the membrane for both ions, only Ca2+ can diffuse down this gradient. Ca2+ will diffuse from solution A to solution B, leaving negative charge behind in solution A. The magnitude of this voltage can be calculated for electrochemical equilibrium with the Nernst equation as follows: ECa2+ = 2.3 RT/zF log CA/CB = 60 mV/+2 log 10 mM/1 mM = 30 mV log 10 = 30 mV. The sign is determined with an intuitive approach—Ca2+ diffuses from solution A to solution B, so solution A develops a negative voltage (–30 mV). Net diffusion of Ca2+ will cease when this voltage is achieved, that is, when the chemical driving force is exactly balanced by the electrical driving force (not when the Ca2+ concentrations of the solutions become equal).

27

98761_Ch01 5/7/10 6:38 PM Page 28

28


8. The answer is B [V B 8]. Myasthenia gravis is characterized by a decreased density of acetylcholine (ACh) receptors at the muscle end plate. An acetylcholinesterase (AChE) inhibitor blocks degradation of ACh in the neuromuscular junction, so levels at the muscle end plate remain high, partially compensating for the deficiency of receptors.

9. The answer is D [III B 2 d]. Lysis of the patient’s red blood cells (RBCs) was caused by entry of water and swelling of the cells to the point of rupture. Water would flow into the RBCs if the extracellular fluid became hypotonic (had a lower osmotic pressure) relative to the intracellular fluid. By definition, isotonic solutions do not cause water to flow into or out of cells because the osmotic pressure is the same on both sides of the cell membrane. Hypertonic solutions would cause shrinkage of the RBCs. 150 mM NaCl and 300 mM mannitol are isotonic. 350 mM mannitol and 150 mM CaCl3 are hypertonic. Because the reflection coefficient of urea is Blood

Na+ Cl– HCO3–

K+ Ca2+ Glucose

Mg2+ Creatinine

Osmolarity

Cholesterol* Protein*

*Negligible concentration in CSF.

C. Functions of the blood–brain barrier 1. It maintains a constant environment for neurons in the CNS and protects the brain from endogenous or exogenous toxins.

2. It prevents the escape of neurotransmitters from their functional sites in the CNS into the general circulation.

3. Drugs penetrate the blood–brain barrier to varying degrees. For example, nonionized (lipid-soluble) drugs cross more readily than ionized (water-soluble) drugs. ■

Inflammation, irradiation, and tumors may destroy the blood–brain barrier and permit entry into the brain of substances that are usually excluded (e.g., antibiotics, radiolabeled markers).

VI. TEMPERATURE REGULATION A. Sources of heat gain and heat loss from the body 1. Heat-generating mechanisms—response to cold a. Thyroid hormone increases metabolic rate and heat production by stimulating Na+, K+adenosine triphosphatase (ATPase).

b. Cold temperatures activate the sympathetic nervous system and, via activation of β receptors in brown fat, increase metabolic rate and heat production.

c. Shivering is the most potent mechanism for increasing heat production. ■ ■

Cold temperatures activate the shivering response, which is orchestrated by the posterior hypothalamus. α-Motoneurons and γ-motoneurons are activated, causing contraction of skeletal muscle and heat production.

2. Heat-loss mechanisms—response to heat a. Heat loss by radiation and convection increases when the ambient temperature increases. ■ ■

The response is orchestrated by the anterior hypothalamus. Increases in temperature cause a decrease in sympathetic tone to cutaneous blood vessels, increasing blood flow through the arterioles and increasing arteriovenous shunting of blood to the venous plexus near the surface of the skin. Shunting of warm blood to the surface of the skin increases heat loss by radiation and convection.

b. Heat loss by evaporation depends on the activity of sweat glands, which are under sympathetic muscarinic control.

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B. Hypothalamic set point for body temperature 1. Temperature sensors on the skin and in the hypothalamus “read” the core temperature and relay this information to the anterior hypothalamus. 2. The anterior hypothalamus compares the detected core temperature to the set-point temperature. a. If the core temperature is below the set point, heat-generating mechanisms (e.g., increased metabolism, shivering, vasoconstriction of cutaneous blood vessels) are activated by the posterior hypothalamus. b. If the core temperature is above the set point, mechanisms for heat loss (e.g., vasodilation of the cutaneous blood vessels, increased sympathetic outflow to the sweat glands) are activated by the anterior hypothalamus. 3. Pyrogens increase the set-point temperature. Core temperature will be recognized as lower than the new set-point temperature by the anterior hypothalamus. As a result, heatgenerating mechanisms (e.g., shivering) will be initiated.

C. Fever 1. Pyrogens increase the production of interleukin-1 (IL-1) in phagocytic cells. ■

IL-1 acts on the anterior hypothalamus to increase the production of prostaglandins. Prostaglandins increase the set-point temperature, setting in motion the heat-generating mechanisms that increase body temperature and produce fever.

2. Aspirin reduces fever by inhibiting cyclooxygenase, thereby inhibiting the production of prostaglandins. Therefore, aspirin decreases the set-point temperature. In response, mechanisms that cause heat loss (e.g., sweating, vasodilation) are activated.

3. Steroids reduce fever by blocking the release of arachidonic acid from brain phospholipids, thereby preventing the production of prostaglandins.

D. Heat exhaustion and heat stroke 1. Heat exhaustion is caused by excessive sweating. As a result, blood volume and arterial blood pressure decrease and syncope (fainting) occurs.

2. Heat stroke occurs when body temperature increases to the point of tissue damage. The normal response to increased ambient temperature (sweating) is impaired, and core temperature increases further.

E. Hypothermia ■

results when the ambient temperature is so low that heat-generating mechanisms (e.g., shivering, metabolism) cannot adequately maintain core temperature near the set point.

F. Malignant hyperthermia ■ ■

is caused in susceptible individuals by inhalation anesthetics. is characterized by a massive increase in oxygen consumption and heat production by skeletal muscle, which causes a rapid rise in body temperature.


Review Test 1. Which autonomic receptor is blocked by hexamethonium at the ganglia, but not at the neuromuscular junction? (A) (B) (C) (D) (E)

Adrenergic α receptors Adrenergic β1 receptors Adrenergic β2 receptors Cholinergic muscarinic receptors Cholinergic nicotinic receptors

2. A 66-year-old man with chronic hypertension is treated with prazosin by his physician. The treatment successfully decreases his blood pressure to within the normal range. What is the mechanism of the drug’s action? (A) Inhibition of β1 receptors in the sinoatrial (SA) node (B) Inhibition of β2 receptors in the SA node (C) Stimulation of muscarinic receptors in the SA node (D) Stimulation of nicotinic receptors in the SA node (E) Inhibition of β1 receptors in ventricular muscle (F) Stimulation of β1 receptors in ventricular muscle (G) Inhibition of α1 receptors in ventricular muscle (H) Stimulation of α1 receptors in the SA node (I) Inhibition of α1 receptors in the SA node (J) Inhibition of α1 receptors on vascular smooth muscle (K) Stimulation of α1 receptors on vascular smooth muscle (L) Stimulation of α2 receptors on vascular smooth muscle

(B) Have the largest diameter of any nerve fiber type (C) Are afferent nerves from muscle spindles (D) Are afferent nerves from Golgi tendon organs (E) Are preganglionic autonomic fibers 5. When compared with the cones of the retina, the rods (A) (B) (C) (D)

are more sensitive to low-intensity light adapt to darkness before the cones are most highly concentrated on the fovea are primarily involved in color vision

6. Which of the following statements best describes the basilar membrane of the organ of Corti? (A) The apex responds better to low frequencies than the base does (B) The base is wider than the apex (C) The base is more compliant than the apex (D) High frequencies produce maximal displacement of the basilar membrane near the helicotrema (E) The apex is relatively stiff compared to the base 7. Which of the following is a feature of the sympathetic, but not the parasympathetic, nervous system?

Dilation of bronchiolar smooth muscle Erection Ejaculation Constriction of gastrointestinal (GI) sphincters (E) Increased cardiac contractility

(A) Ganglia located in the effector organs (B) Long preganglionic neurons (C) Preganglionic neurons release norepinephrine (D) Preganglionic neurons release acetylcholine (ACh) (E) Preganglionic neurons originate in the thoracolumbar spinal cord (F) Postganglionic neurons synapse on effector organs (G) Postganglionic neurons release epinephrine (H) Postganglionic neurons release ACh

4. Which of the following is a property of C fibers?

8. Which autonomic receptor mediates an increase in heart rate?

(A) Have the slowest conduction velocity of any nerve fiber type

(A) Adrenergic α receptors (B) Adrenergic β1 receptors

3. Which of the following responses is mediated by parasympathetic muscarinic receptors? (A) (B) (C) (D)

57


58


(C) Adrenergic β2 receptors (D) Cholinergic muscarinic receptors (E) Cholinergic nicotinic receptors

15. Which of the following parts of the body has cortical motoneurons with the largest representation on the primary motor cortex (area 4)?

9. Cutting which structure on the left side causes total blindness in the left eye?

(A) (B) (C) (D) (E)

(A) (B) (C) (D)

Optic nerve Optic chiasm Optic tract Geniculocalcarine tract

10. Which reflex is responsible for monosynaptic excitation of ipsilateral homonymous muscle? (A) (B) (C) (D)

Stretch reflex (myotatic) Golgi tendon reflex (inverse myotatic) Flexor withdrawal reflex Subliminal occlusion reflex

11. Which type of cell in the visual cortex responds best to a moving bar of light? (A) (B) (C) (D) (E)

Simple Complex Hypercomplex Bipolar Ganglion

12. Administration of which of the following drugs is contraindicated in a 10-year-old child with a history of asthma? (A) (B) (C) (D) (E)

Albuterol Epinephrine Isoproterenol Norepinephrine Propranolol

13. Which adrenergic receptor produces its stimulatory effects by the formation of inositol 1,4,5-triphosphate (IP3) and an increase in intracellular [Ca2+]? (A) (B) (C) (D) (E) (F)

α1 Receptors α2 Receptors β1 Receptors β2 Receptors Muscarinic receptors Nicotinic receptors

14. The excessive muscle tone produced in decerebrate rigidity can be reversed by (A) stimulation of group Ia afferents (B) cutting the dorsal roots (C) transection of cerebellar connections to the lateral vestibular nucleus (D) stimulation of α-motoneurons (E) stimulation of γ-motoneurons

Shoulder Ankle Fingers Elbow Knee

16. Which autonomic receptor mediates secretion of epinephrine by the adrenal medulla? (A) (B) (C) (D) (E)


17. Cutting which structure on the right side causes blindness in the temporal field of the left eye and the nasal field of the right eye? (A) (B) (C) (D)


18. A ballet dancer spins to the left. During the spin, her eyes snap quickly to the left. This fast eye movement is (A) (B) (C) (D)

nystagmus postrotatory nystagmus ataxia aphasia

19. Which of the following has a much lower concentration in the cerebrospinal fluid (CSF) than in cerebral capillary blood? (A) (B) (C) (D) (E)

Na+ K+ Osmolarity Protein Mg2+

20. Which of the following autonomic drugs acts by stimulating adenylate cyclase? (A) (B) (C) (D) (E) (F) (G)

Atropine Clonidine Curare Norepinephrine Phentolamine Phenylephrine Propranolol


Chapter 2 Neurophysiology 21. Which of the following is a step in photoreception in the rods? (A) Light converts all-trans rhodopsin to 11-cis rhodopsin (B) Metarhodopsin II activates transducin (C) Cyclic guanosine monophosphate (cGMP) levels increase (D) Rods depolarize (E) Release of neurotransmitter increases 22. Pathogens that produce fever cause (A) decreased production of interleukin-1 (IL-1) (B) decreased set-point temperature in the hypothalamus (C) shivering (D) vasodilation of blood vessels in the skin 23. Which of the following statements about the olfactory system is true? (A) The receptor cells are neurons (B) The receptor cells are sloughed off and are not replaced (C) Axons of cranial nerve (CN) I are A-delta fibers (D) Axons from receptor cells synapse in the prepiriform cortex (E) Fractures of the cribriform plate can cause inability to detect ammonia 24. A lesion of the chorda tympani nerve would most likely result in (A) (B) (C) (D) (E)

impaired olfactory function impaired vestibular function impaired auditory function impaired taste function nerve deafness

25. Which of the following would produce maximum excitation of the hair cells in the right horizontal semicircular canal? (A) Hyperpolarization of the hair cells (B) Bending the stereocilia away from the kinocilia (C) Rapid ascent in an elevator (D) Rotating the head to the right 26. The inability to perform rapidly alternating movements (dysdiadochokinesia) is associated with lesions of the (A) (B) (C) (D) (E)

premotor cortex motor cortex cerebellum substantia nigra medulla

59

27. Which autonomic receptor is activated by low concentrations of epinephrine released from the adrenal medulla and causes vasodilation? (A) (B) (C) (D) (E)


28. Complete transection of the spinal cord at the level of T1 would most likely result in (A) temporary loss of stretch reflexes below the lesion (B) temporary loss of conscious proprioception below the lesion (C) permanent loss of voluntary control of movement above the lesion (D) permanent loss of consciousness above the lesion 29. Sensory receptor potentials (A) are action potentials (B) always bring the membrane potential of a receptor cell toward threshold (C) always bring the membrane potential of a receptor cell away from threshold (D) are graded in size, depending on stimulus intensity (E) are all-or-none 30. Cutting which structure causes blindness in the temporal fields of the left and right eyes? (A) (B) (C) (D)


31. Which of the following structures has a primary function to coordinate rate, range, force, and direction of movement? (A) Primary motor cortex (B) Premotor cortex and supplementary motor cortex (C) Prefrontal cortex (D) Basal ganglia (E) Cerebellum 32. Which reflex is responsible for polysynaptic excitation of contralateral extensors? (A) (B) (C) (D)

Stretch reflex (myotatic) Golgi tendon reflex (inverse myotatic) Flexor withdrawal reflex Subliminal occlusion reflex


60


33. Which of the following is a characteristic of nuclear bag fibers? (A) They are one type of extrafusal muscle fiber (B) They detect dynamic changes in muscle length (C) They give rise to group Ib afferents (D) They are innervated by α-motoneurons 34. Muscle stretch leads to a direct increase in firing rate of which type of nerve? (A) (B) (C) (D)

α-Motoneurons γ-Motoneurons Group Ia fibers Group Ib fibers

35. A 42-year-old woman with elevated blood pressure, visual disturbances, and

vomiting has increased urinary excretion of 3-methoxy-4-hydroxymandelic acid (VMA). A computerized tomographic scan shows an adrenal mass that is consistent with a diagnosis of pheochromocytoma. While awaiting surgery to remove the tumor, she is treated with phenoxybenzamine to lower her blood pressure. What is the mechanism of this action of the drug? (A) Increasing cyclic adenosine monophosphate (cAMP) (B) Decreasing cAMP (C) Increasing inositol 1,4,5-triphosphate (IP3)/Ca2+ (D) Decreasing IP3/Ca2+ (E) Opening Na+/K+ channels (F) Closing Na+/K+ channels


Answers and Explanations 1. The answer is E [I C 2 a]. Hexamethonium is a nicotinic blocker, but it acts only at ganglionic (not neuromuscular junction) nicotinic receptors. This pharmacologic distinction emphasizes that nicotinic receptors at these two locations, although similar, are not identical. 2. The answer is J [I C 1 a; Table 2-2]. Prazosin is a specific antagonist of α1 receptors, which are present in vascular smooth muscle, but not in the heart. Inhibition of α1 receptors results in vasodilation of the cutaneous and splanchnic vascular beds, decreased total peripheral resistance, and decreased blood pressure. 3. The answer is B [I C 2 b; Table 2-4]. Erection is a parasympathetic muscarinic response. Dilation of the bronchioles, ejaculation, constriction of the gastrointestinal (GI) sphincters, and increased cardiac contractility are all sympathetic α or β responses. 4. The answer is A [II F 1 b; Table 2-5]. C fibers (slow pain) are the smallest nerve fibers and therefore have the slowest conduction velocity. 5. The answer is A [II C 2 c (2); Table 2-7]. Of the two types of photoreceptors, the rods are more sensitive to low-intensity light and therefore are more important than the cones for night vision. They adapt to darkness after the cones. Rods are not present in the fovea. The cones are primarily involved in color vision. 6. The answer is A [II D 4]. Sound frequencies can be encoded by the organ of Corti because of differences in properties along the basilar membrane. The base of the basilar membrane is narrow and stiff, and hair cells on it are activated by high frequencies. The apex of the basilar membrane is wide and compliant, and hair cells on it are activated by low frequencies. 7. The answer is E [I A, B; Table 2-1; Figure 2-1]. Sympathetic preganglionic neurons originate in spinal cord segments T1–L3. Thus, the designation is thoracolumbar. The sympathetic nervous system is further characterized by short preganglionic neurons that synapse in ganglia located in the paravertebral chain (not in the effector organs) and postganglionic neurons that release norepinephrine (not epinephrine). Common features of the sympathetic and parasympathetic nervous systems are preganglionic neurons that release acetylcholine (ACh) and postganglionic neurons that synapse in effector organs. 8. The answer is B [I C 1 c]. Heart rate is increased by the stimulatory effect of norepinephrine on β1 receptors in the sinoatrial (SA) node. There are also sympathetic β1 receptors in the heart that regulate contractility. 9. The answer is A [II C 3 a]. Cutting the optic nerve from the left eye causes blindness in the left eye because the fibers have not yet crossed at the optic chiasm. 10. The answer is A [III C 1]. The stretch reflex is the monosynaptic response to stretching of a muscle. The reflex produces contraction and then shortening of the muscle that was originally stretched (homonymous muscle). 11. The answer is B [II C 5 b (2)]. Complex cells respond to moving bars or edges with the correct orientation. Simple cells respond to stationary bars, and hypercomplex cells respond to lines, curves, and angles. Bipolar and ganglion cells are found in the retina, not in the visual cortex. 12. The answer is E [I C 1 d; Table 2-2]. Asthma, a disease involving increased resistance of the upper airways, is treated by administering drugs that produce bronchiolar dilation (i.e., β2 agonists). β2 Agonists include isoproterenol, albuterol, epinephrine, and, to a lesser extent, norepinephrine. β2 Antagonists, such as propranolol, are strictly contraindicated because they cause constriction of the bronchioles.

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62


13. The answer is A [I C 1 a]. Adrenergic α1 receptors produce physiologic actions by stimulating the formation of inositol 1,4,5-triphosphate (IP3) and causing a subsequent increase in intracellular [Ca2+]. Both β1 and β2 receptors act by stimulating adenylate cyclase and increasing the production of cyclic adenosine monophosphate (cAMP). α2 Receptors inhibit adenylate cyclase and decrease cAMP levels. Muscarinic and nicotinic receptors are cholinergic. 14. The answer is B [III E 3 a, b]. Decerebrate rigidity is caused by increased reflex muscle spindle activity. Stimulation of group Ia afferents would enhance, not diminish, this reflex activity. Cutting the dorsal roots would block the reflexes. Stimulation of α- and γ-motoneurons would stimulate muscles directly. 15. The answer is C [II B 4]. Representation on the motor homunculus is greatest for those structures that are involved in the most complicated movements—the fingers, hands, and face. 16. The answer is E [I C 2 a; Figure 2-1]. Preganglionic sympathetic fibers synapse on the chromaffin cells of the adrenal medulla at a nicotinic receptor. Epinephrine and, to a lesser extent, norepinephrine are released into the circulation. 17. The answer is C [II C 3 c]. Fibers from the left temporal field and the right nasal field ascend together in the right optic tract. 18. The answer is A [II E 3]. The fast eye movement that occurs during a spin is nystagmus. It occurs in the same direction as the rotation. After the spin, postrotatory nystagmus occurs in the opposite direction. 19. The answer is D [V B; Table 2-9]. Cerebrospinal fluid (CSF) is similar in composition to the interstitial fluid of the brain. Therefore, it is similar to an ultrafiltrate of plasma and has a very low protein concentration because large protein molecules cannot cross the blood–brain barrier. There are other differences in composition between CSF and blood that are created by transporters in the choroid plexus, but the low protein concentration of CSF is the most dramatic difference. 20. The answer is D [I C 1 c, d; Table 2-2]. Among the autonomic drugs, only β1 and β2 adrenergic agonists act by stimulating adenylate cyclase. Norepinephrine is a β1 agonist. Atropine is a muscarinic cholinergic antagonist. Clonidine is an α2 adrenergic agonist. Curare is a nicotinic cholinergic antagonist. Phentolamine is an α1 adrenergic antagonist. Phenylephrine is an α1 adrenergic agonist. Propranolol is a β1 and β2 adrenergic antagonist. 21. The answer is B [II C 4]. Photoreception involves the following steps. Light converts 11-cis rhodopsin to all-trans rhodopsin, which is converted to such intermediates as metarhodopsin II. Metarhodopsin II activates a stimulatory G protein (transducin), which activates a phosphodiesterase. Phosphodiesterase breaks down cyclic guanosine monophosphate (cGMP), so intracellular cGMP levels decrease, causing closure of Na+ channels in the photoreceptor cell membrane and hyperpolarization. Hyperpolarization of the photoreceptor cell membrane inhibits the release of neurotransmitter. If the neurotransmitter is excitatory, then the bipolar cell will be hyperpolarized (inhibited). If the neurotransmitter is inhibitory, then the bipolar cell will be depolarized (excited). 22. The answer is C [VI C 1]. Pathogens release interleukin-1 (IL-1) from phagocytic cells. IL-1 then acts to increase the production of prostaglandins, ultimately raising the temperature set point in the anterior hypothalamus. The hypothalamus now “thinks” that the body temperature is too low (because the core temperature is lower than the new set-point temperature) and initiates mechanisms for generating heat—shivering, vasoconstriction, and shunting of blood away from the venous plexus near the skin surface. 23. The answer is A [II F 1 a, b]. Cranial nerve (CN) I innervates the olfactory epithelium. Its axons are C fibers. Fracture of the cribriform plate can tear the delicate olfactory nerves and thereby eliminate the sense of smell (anosmia); however, the ability to detect ammonia is left intact. Olfactory receptor cells are unique in that they are true neurons that are continuously replaced from undifferentiated stem cells.


Chapter 2 Neurophysiology

63

24. The answer is D [II G 1 b]. The chorda tympani [cranial nerve (CN) VII] is involved in taste; it innervates the anterior two-thirds of the tongue. 25. The answer is D [II E 1 a, 2 a, b]. The semicircular canals are involved in angular acceleration or rotation. Hair cells of the right semicircular canal are excited (depolarized) when there is rotation to the right. This rotation causes bending of the stereocilia toward the kinocilia, and this bending produces depolarization of the hair cell. Ascent in an elevator would activate the saccules, which detect linear acceleration. 26. The answer is C [III F 1 c, 3 c]. Coordination of movement (synergy) is the function of the cerebellum. Lesions of the cerebellum cause ataxia, lack of coordination, poor execution of movement, delay in initiation of movement, and inability to perform rapidly alternating movements. The premotor and motor cortices plan and execute movements. Lesions of the substantia nigra, a component of the basal ganglia, result in tremors, lead-pipe rigidity, and poor muscle tone (Parkinson’s disease). 27. The answer is C [I C 1 d]. β2 Receptors on vascular smooth muscle produce vasodilation. α Receptors on vascular smooth muscle produce vasoconstriction. Because β2 receptors are more sensitive to epinephrine than are α receptors, low doses of epinephrine produce vasodilation, and high doses produce vasoconstriction. 28. The answer is A [III E 2]. Transection of the spinal cord causes “spinal shock” and loss of all reflexes below the level of the lesion. These reflexes, which are local circuits within the spinal cord, will return with time or become hypersensitive. Proprioception is permanently (rather than temporarily) lost because of the interruption of sensory nerve fibers. Fibers above the lesion are intact. 29. The answer is D [II A 4 c]. Receptor potentials are graded potentials that may bring the membrane potential of the receptor cell either toward (depolarizing) or away from (hyperpolarizing) threshold. Receptor potentials are not action potentials, although action potentials (which are all-or-none) may result if the membrane potential reaches threshold. 30. The answer is B [II C 3 b]. Optic nerve fibers from both temporal receptor fields cross at the optic chiasm. 31. The answer is E [III F 3 b]. Output of Purkinje cells from the cerebellar cortex to deep cerebellar nuclei is inhibitory. This output modulates movement and is responsible for the coordination that allows one to “catch a fly.” 32. The answer is C [III C 3]. Flexor withdrawal is a polysynaptic reflex that is used when a person touches a hot stove or steps on a tack. On the ipsilateral side of the painful stimulus, there is flexion (withdrawal); on the contralateral side, there is extension to maintain balance. 33. The answer is B [III B 3 a (1)]. Nuclear bag fibers are one type of intrafusal muscle fiber that make up muscle spindles. They detect dynamic changes in muscle length, give rise to group Ia afferent fibers, and are innervated by γ-motoneurons. The other type of intrafusal fiber, the nuclear chain fiber, detects static changes in muscle length. 34. The answer is C [III B 3 b]. Group Ia afferent fibers innervate intrafusal fibers of the muscle spindle. When the intrafusal fibers are stretched, the group Ia fibers fire and activate the stretch reflex, which causes the muscle to return to its resting length. 35. The answer is D (I C; Table 2-2; Table 2-3). Pheochromocytoma is a tumor of the adrenal medulla that secretes excessive amounts of norepinephrine and epinephrine. Increased blood pressure is due to activation of α1 receptors on vascular smooth muscle and activation of β1 receptors in the heart. Phenoxybenzamine decreases blood pressure by acting as an α1 receptor antagonist, thus decreasing intracellular IP3/Ca2+.


chapter

3

Cardiovascular Physiology

I. CIRCUITRY OF THE CARDIOVASCULAR SYSTEM (FIGURE 3-1) A. Cardiac output of the left heart equals cardiac output of the right heart. ■ ■

Cardiac output from the left side of the heart is the systemic blood flow. Cardiac output from the right side of the heart is the pulmonary blood flow.

B. Direction of blood flow ■

Blood flows along the following course:

1. 2. 3. 4. 5. 6. 7. 8. 9.

From the lungs to the left atrium via the pulmonary vein From the left atrium to the left ventricle through the mitral valve From the left ventricle to the aorta through the aortic valve From the aorta to the systemic arteries and the systemic tissues (i.e., cerebral, coronary, renal, splanchnic, skeletal muscle, and skin) From the tissues to the systemic veins and vena cava From the vena cava (mixed venous blood) to the right atrium From the right atrium to the right ventricle through the tricuspid valve From the right ventricle to the pulmonary artery through the pulmonic valve From the pulmonary artery to the lungs for oxygenation

II. HEMODYNAMICS A. Components of the vasculature 1. Arteries ■ ■ ■ ■

deliver oxygenated blood to the tissues. are thick-walled, with extensive elastic tissue and smooth muscle. are under high pressure. The blood volume contained in the arteries is called the stressed volume.

2. Arterioles ■ ■ ■ ■ ■ ■

64

are the smallest branches of the arteries. are the site of highest resistance in the cardiovascular system. have a smooth muscle wall that is extensively innervated by autonomic nerve fibers. Arteriolar resistance is regulated by the autonomic nervous system (ANS). α1-Adrenergic receptors are found on the arterioles of the skin, splanchnic, and renal circulations. β2-Adrenergic receptors are found on arterioles of skeletal muscle.


65

Chapter 3 Cardiovascular Physiology Pulmonary artery

Lungs

Pulmonary vein

Right atrium

Left atrium

Right ventricle

Left ventricle

Vena cava

Aorta Cerebral Coronary Systemic veins

Renal

Systemic arteries

Splanchnic Skeletal muscle Skin FIGURE 3-1 Circuitry of the cardiovascular system.

3. Capillaries ■ ■ ■ ■

have the largest total cross-sectional and surface area. consist of a single layer of endothelial cells surrounded by basal lamina. are thin-walled. are the site of exchange of nutrients, water, and gases.

4. Venules ■

are formed from merged capillaries.

5. Veins ■ ■ ■ ■ ■ ■

progressively merge to form larger veins. The largest vein, the vena cava, returns blood to the heart. are thin-walled. are under low pressure. contain the highest proportion of the blood in the cardiovascular system. The blood volume contained in the veins is called the unstressed volume. have α1-adrenergic receptors.

B. Velocity of blood flow ■

can be expressed by the following equation: v ⴝQ A where: v = velocity (cm/sec) Q = blood flow (mL/min) A = cross-sectional area (cm2)

■

Velocity is directly proportional to blood flow and inversely proportional to the crosssectional area at any level of the cardiovascular system.


66


For example, blood velocity is higher in the aorta (small cross-sectional area) than in the sum of all of the capillaries (large cross-sectional area). The lower velocity of blood in the capillaries optimizes conditions for exchange of substances across the capillary wall.

C. Blood flow ■

can be expressed by the following equation: Q ⴝ ⌬P R or Cardiac output ⴝ

Mean arterial pressure ⴚ Right atrial pressure Total peripheral resistan ce (TPR)

where: Q = flow or cardiac output (mL/min) ΔP = pressure gradient (mm Hg) R = resistance or total peripheral resistance (mm Hg/mL/min) ■ ■ ■ ■

The equation for blood flow (or cardiac output) is analogous to Ohm’s law for electrical circuits (I = V/R), where flow is analogous to current, and pressure is analogous to voltage. The pressure gradient (ΔP) drives blood flow. Thus, blood flows from high pressure to low pressure. Blood flow is inversely proportional to the resistance of the blood vessels.

D. Resistance ■

Poiseuille’s equation gives factors that change the resistance of blood vessels. R ⴝ

8 gl o r4

where: R = resistance η = viscosity of blood l = length of blood vessel r4 = radius of blood vessel to the fourth power ■ ■ ■

Resistance is directly proportional to the viscosity of the blood. For example, increasing viscosity by increasing hematocrit will increase resistance and decrease blood flow. Resistance is directly proportional to the length of the vessel. Resistance is inversely proportional to the fourth power of the vessel radius. This relationship is powerful. For example, if blood vessel radius decreases by a factor of 2, then resistance increases by a factor of 16 (24), and blood flow accordingly decreases by a factor of 16.

1. Resistances in parallel or series a. Parallel resistance is illustrated by the systemic circulation. Each organ is supplied by an artery that branches off the aorta. The total resistance of this parallel arrangement is expressed by the following equation: 1 1 1 ... 1 = + + + Rtotal Ra Rb Rn Ra, Rb, and Rn are the resistances of the renal, hepatic, and other arteries, respectively. ■ ■ ■ ■

Each artery in parallel receives a fraction of the total blood flow. The total resistance is less than the resistance of any of the individual arteries. When an artery is added in parallel, the total resistance decreases. In each parallel artery, the pressure is the same.

b. Series resistance is illustrated by the arrangement of blood vessels within a given organ. Each organ is supplied by a large artery, smaller arteries, arterioles, capillaries,


Chapter 3 Cardiovascular Physiology

67

and veins arranged in series. The total resistance is the sum of the individual resistances, as expressed by the following equation: Rtotal = Rartery + Rarterioles + Rcapillaries ■ ■

■

The largest proportion of resistance in this series is contributed by the arterioles. Each blood vessel (e.g., the largest artery) or set of blood vessels (e.g., all of the capillaries) in series receives the same total blood flow. Thus, blood flow through the largest artery is the same as the total blood flow through all of the capillaries. As blood flows through the series of blood vessels, the pressure decreases.

2. Laminar flow versus turbulent flow ■ ■ ■

Laminar flow is streamlined (in a straight line); turbulent flow is not. Reynolds number predicts whether blood flow will be laminar or turbulent. When Reynolds number is increased, there is a greater tendency for turbulence, which causes audible vibrations called bruits. Reynolds number (and therefore turbulence) is increased by the following factors:

a. ↓ blood viscosity (e.g., ↓ hematocrit, anemia) b. ↑ blood velocity (e.g., narrowing of a vessel) 3. Shear ■ ■ ■

Is a consequence of the fact that blood travels at different velocities within a blood vessel. Velocity of blood is zero at the wall and highest at the center of the vessel. Shear is therefore highest at the wall, where the difference in blood velocity is greatest and lowest at the center of the vessel, where blood velocity is constant.

E. Capacitance (compliance) ■ ■ ■

describes the distensibility of blood vessels. is inversely related to elastance, or stiffness. The greater the amount of elastic tissue there is in a blood vessel, the higher the elastance is, and the lower the compliance is. is expressed by the following equation: Cⴝ

V P

where: C = capacitance, or compliance (mL/mm Hg) V = volume (mL) P = pressure (mm Hg) ■ ■ ■ ■

■

is directly proportional to volume and inversely proportional to pressure. describes how volume changes in response to a change in pressure. is much greater for veins than for arteries. As a result, more blood volume is contained in the veins (unstressed volume) than in the arteries (stressed volume). Changes in the capacitance of the veins produce changes in unstressed volume. For example, a decrease in venous capacitance decreases unstressed volume and increases stressed volume by shifting blood from the veins to the arteries. Capacitance of the arteries decreases with age; as a person ages, the arteries become stiffer and less distensible.

F. Pressure profile in blood vessels ■ ■

As blood flows through the systemic circulation, pressure decreases progressively because of the resistance to blood flow. Thus, pressure is highest in the aorta and large arteries and lowest in the venae cavae.


68

Board Review Series: Physiology ■ ■

The largest decrease in pressure occurs across the arterioles because they are the site of highest resistance. Mean pressures in the systemic circulation are as follows:

1. 2. 3. 4.

Aorta, 100 mm Hg Arterioles, 50 mm Hg Capillaries, 20 mm Hg Vena cava, 4 mm Hg

G. Arterial pressure (Figure 3-2) ■ ■

is pulsatile. is not constant during a cardiac cycle.

1. Systolic pressure ■ ■

is the highest arterial pressure during a cardiac cycle. is measured after the heart contracts (systole) and blood is ejected into the arterial system.

2. Diastolic pressure ■ ■

is the lowest arterial pressure during a cardiac cycle. is measured when the heart is relaxed (diastole) and blood is returned to the heart via the veins.

3. Pulse pressure ■ ■

■

is the difference between the systolic and diastolic pressures. The most important determinant of pulse pressure is stroke volume. As blood is ejected from the left ventricle into the arterial system, arterial pressure increases because of the relatively low capacitance of the arteries. Because diastolic pressure remains unchanged during ventricular systole, the pulse pressure increases to the same extent as the systolic pressure. Decreases in capacitance, such as those that occur with the aging process, cause increases in pulse pressure.

Arterial pressure (mm Hg)

120

Systolic pressure

Mean pressure Diastolic pressure

80

40

0 Time FIGURE 3-2 Arterial pressure during the cardiac cycle.

Pulse pressure



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4. Mean arterial pressure ■ ■

is the average arterial pressure with respect to time. can be calculated approximately as diastolic pressure plus one-third of pulse pressure.

H. Venous pressure ■ ■

is very low. The veins have a high capacitance and, therefore, can hold large volumes of blood at low pressure.

I. Atrial pressure ■ ■

is slightly lower than venous pressure. Left atrial pressure is estimated by the pulmonary wedge pressure. A catheter, inserted into the smallest branches of the pulmonary artery, makes almost direct contact with the pulmonary capillaries. The measured pulmonary capillary pressure is approximately equal to the left atrial pressure.

III. CARDIAC ELECTROPHYSIOLOGY A. Electrocardiogram (ECG) (Figure 3-3) 1. P wave ■ ■

represents atrial depolarization. does not include atrial repolarization, which is “buried” in the QRS complex.

2. PR interval ■

is the interval from the beginning of the P wave to the beginning of the Q wave (initial depolarization of the ventricle).

R

T P

Q

ST

PR S

QT

FIGURE 3-3 Normal electrocardiogram measured from lead II.


70

Board Review Series: Physiology ■ ■ ■

varies with conduction velocity through the atrioventricular (AV) node. For example, if AV nodal conduction decreases (as in heart block), the PR interval increases. is decreased (i.e., increased conduction velocity through AV node) by stimulation of the sympathetic nervous system. is increased (i.e., decreased conduction velocity through AV node) by stimulation of the parasympathetic nervous system.

3. QRS complex ■

represents depolarization of the ventricles.

4. QT interval ■ ■

is the interval from the beginning of the Q wave to the end of the T wave. represents the entire period of depolarization and repolarization of the ventricles.

5. ST segment ■ ■ ■

is the segment from the end of the S wave to the beginning of the T wave. is isoelectric. represents the period when the ventricles are depolarized.

6. T wave ■

represents ventricular repolarization.

B. Cardiac action potentials (see Table 1-3) ■ ■ ■ ■

The resting membrane potential is determined by the conductance to K+ and approaches the K+ equilibrium potential. Inward current brings positive charge into the cell and depolarizes the membrane potential. Outward current takes positive charge out of the cell and hyperpolarizes the membrane potential. The role of Na+,K+-adenosine triphosphatase (ATPase) is to maintain ionic gradients across cell membranes.

1. Ventricles, atria, and the Purkinje system (Figure 3-4) ■ ■

have stable resting membrane potentials of about –90 millivolts (mV). This value approaches the K+ equilibrium potential. Action potentials are of long duration, especially in Purkinje fibers, where they last 300 milliseconds (msec).

a. Phase 0 ■

is the upstroke of the action potential.

+40 +20

1

2 ICa

Millivolts

0 –20 –40

0 INa

3 IK

–60 –80

4 IK1

–100 100 msec FIGURE 3-4 Ventricular action potential.


Chapter 3 Cardiovascular Physiology ■ ■

71

is caused by a transient increase in Na+ conductance. This increase results in an inward Na+ current that depolarizes the membrane. At the peak of the action potential, the membrane potential approaches the Na+ equilibrium potential.

b. Phase 1 ■ ■

is a brief period of initial repolarization. Initial repolarization is caused by an outward current, in part because of the movement of K+ ions (favored by both chemical and electrical gradients) out of the cell and in part because of a decrease in Na+ conductance.

c. Phase 2 ■ ■ ■

is the plateau of the action potential. is caused by a transient increase in Ca2+ conductance, which results in an inward Ca2+ current, and by an increase in K+ conductance. During phase 2, outward and inward currents are approximately equal, so the membrane potential is stable at the plateau level.

d. Phase 3 ■ ■ ■

is repolarization. During phase 3, Ca2+ conductance decreases, and K+ conductance increases and therefore predominates. The high K+ conductance results in a large outward K+ current (IK), which hyperpolarizes the membrane back toward the K+ equilibrium potential.

e. Phase 4 ■ ■

is the resting membrane potential. is a period during which inward and outward currents (IK1) are equal and the membrane potential approaches the K+ equilibrium potential.

2. Sinoatrial (SA) node (Figure 3-5) ■ ■ ■ ■ ■

is normally the pacemaker of the heart. has an unstable resting potential. exhibits phase 4 depolarization, or automaticity. The AV node and the His-Purkinje systems are latent pacemakers that may exhibit automaticity and override the SA node if it is suppressed. The intrinsic rate of phase 4 depolarization (and heart rate) is fastest in the SA node and slowest in the His-Purkinje system: SA node > AV node > His-Purkinje

0

Millivolts

–20 0 ICa –40 –60

3 IK 4 If

–80 100 msec FIGURE 3-5 Sinoatrial nodal action potential.


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a. Phase 0 ■ ■ ■

is the upstroke of the action potential. is caused by an increase in Ca2+ conductance. This increase causes an inward Ca2+ current that drives the membrane potential toward the Ca2+ equilibrium potential. The ionic basis for phase 0 in the SA node is different from that in the ventricles, atria, and Purkinje fibers (where it is the result of an inward Na+ current).

b. Phase 3 ■ ■

is repolarization. is caused by an increase in K+ conductance. This increase results in an outward K+ current that causes repolarization of the membrane potential.

c. Phase 4 ■ ■ ■ ■

is slow depolarization. accounts for the pacemaker activity of the SA node (automaticity). is caused by an increase in Na+ conductance, which results in an inward Na+ current called If. If is turned on by repolarization of the membrane potential during the preceding action potential.

d. Phases 1 and 2 ■

are not present in the SA node action potential.

3. AV node ■

Upstroke of the action potential in the AV node is the result of an inward Ca+ current (as in the SA node).

C. Conduction velocity ■ ■ ■ ■

reflects the time required for excitation to spread throughout cardiac tissue. depends on the size of the inward current during the upstroke of the action potential. The larger the inward current, the higher the conduction velocity. is fastest in the Purkinje system. is slowest in the AV node (seen as the PR interval on the ECG), allowing time for ventricular filling before ventricular contraction. If conduction velocity through the AV node is increased, ventricular filling may be compromised.

D. Excitability ■ ■ ■

is the ability of cardiac cells to initiate action potentials in response to inward, depolarizing current. reflects the recovery of channels that carry the inward currents for the upstroke of the action potential. changes over the course of the action potential. These changes in excitability are described by refractory periods (Figure 3-6).

1. Absolute refractory period (ARP) ■ ■

begins with the upstroke of the action potential and ends after the plateau. reflects the time during which no action potential can be initiated, regardless of how much inward current is supplied.

2. Effective refractory period (ERP) ■ ■

is slightly longer than the ARP. is the period during which a conducted action potential cannot be elicited.

3. Relative refractory period (RRP) ■

is the period immediately after the ARP when repolarization is almost complete.


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Membrane potential (mV)

+20

RRP

–20 –40

ARP

–60

ERP

–80 –100

FIGURE 3-6 Absolute (ARP), effective (ERP), and relative refractory periods (RRP) in the ventricle. ■

0

100 msec

is the period during which an action potential can be elicited, but more than the usual inward current is required.

E. Autonomic effects on heart rate and conduction velocity (Table 3-1) ■

See IV C for a discussion of inotropic effects.

1. Definitions of chronotropic and dromotropic effects a. Chronotropic effects ■ ■ ■

produce changes in heart rate. A negative chronotropic effect decreases heart rate by decreasing the firing rate of the SA node. A positive chronotropic effect increases heart rate by increasing the firing rate of the SA node.

b. Dromotropic effects ■ ■

■

produce changes in conduction velocity, primarily in the AV node. A negative dromotropic effect decreases conduction velocity through the AV node, slowing the conduction of action potentials from the atria to the ventricles and increasing the PR interval. A positive dromotropic effect increases conduction velocity through the AV node, speeding the conduction of action potentials from the atria to the ventricles and decreasing the PR interval.

2. Parasympathetic effects on heart rate and conduction velocity ■

The SA node, atria, and AV node have parasympathetic vagal innervation, but the ventricles do not. The neurotransmitter is acetylcholine (ACh), which acts at muscarinic receptors.

t a b l e

3-1

Autonomic Effects on the Heart and Blood Vessels Sympathetic

Heart rate Conduction velocity (AV node) Contractility Vascular smooth muscle Skin, splanchnic Skeletal muscle AV = atrioventricular.

Parasympathetic

Effect

Receptor

Effect

Receptor

↑ ↑ ↑

β1 β1 β1

↓ ↓ ↓ (atria only)

Muscarinic Muscarinic Muscarinic

Constriction Constriction Relaxation

α1 α1 β2


74


a. Negative chronotropic effect ■ ■ ■

decreases heart rate by decreasing the rate of phase 4 depolarization. Fewer action potentials occur per unit time because the threshold potential is reached more slowly and, therefore, less frequently. The mechanism of the negative chronotropic effect is decreased If, the inward Na+ current that is responsible for phase 4 depolarization in the SA node.

b. Negative dromotropic effect ■ ■ ■ ■

decreases conduction velocity through the AV node. Action potentials are conducted more slowly from the atria to the ventricles. increases the PR interval. The mechanism of the negative dromotropic effect is decreased inward Ca2+ current and increased outward K+ current.

3. Sympathetic effects on heart rate and conduction velocity ■

Norepinephrine is the neurotransmitter, acting at a1 receptors.

a. Positive chronotropic effect ■ ■ ■

increases heart rate by increasing the rate of phase 4 depolarization. More action potentials occur per unit time because the threshold potential is reached more quickly and, therefore, more frequently. The mechanism of the positive chronotropic effect is increased If, the inward Na+ current that is responsible for phase 4 depolarization in the SA node.

b. Positive dromotropic effect

IV.

■

increases conduction velocity through the AV node.

■

Action potentials are conducted more rapidly from the atria to the ventricles, and ventricular filling may be compromised.

■

decreases the PR interval.

■

The mechanism of the positive dromotropic effect is increased inward Ca2+ current.

CARDIAC MUSCLE AND CARDIAC OUTPUT

A. Myocardial cell structure 1. Sarcomere ■ ■ ■ ■ ■

is the contractile unit of the myocardial cell. is similar to the contractile unit in skeletal muscle. runs from Z line to Z line. contains thick filaments (myosin) and thin filaments (actin, troponin, tropomyosin). As in skeletal muscle, shortening occurs according to a sliding filament model, which states that thin filaments slide along adjacent thick filaments by forming and breaking cross-bridges between actin and myosin.

2. Intercalated disks ■ ■

occur at the ends of the cells. maintain cell-to-cell cohesion.

3. Gap junctions ■ ■ ■

are present at the intercalated disks. are low-resistance paths between cells that allow for rapid electrical spread of action potentials. account for the observation that the heart behaves as an electrical syncytium.



75

4. Mitochondria ■

are more numerous in cardiac muscle than in skeletal muscle.

5. T tubules ■ ■ ■ ■

are continuous with the cell membrane. invaginate the cells at the Z lines and carry action potentials into the cell interior. are well developed in the ventricles, but poorly developed in the atria. form dyads with the sarcoplasmic reticulum.

6. Sarcoplasmic reticulum (SR) ■ ■

are small-diameter tubules in close proximity to the contractile elements. are the site of storage and release of Ca2+ for excitation–contraction coupling.

B. Steps in excitation–contraction coupling 1. The action potential spreads from the cell membrane into the T tubules. 2. During the plateau of the action potential, Ca2+ conductance is increased and Ca2+ enters the cell from the extracellular fluid (inward Ca2+ current) through L-type Ca2+ channels (dihydropyridine receptors). 3. This Ca2+ entry triggers the release of even more Ca2+ from the SR (Ca2+-induced Ca2+ release) through Ca2+ release channels (ryanodine receptors). ■

The amount of Ca2+ released from the SR depends on the amount of Ca2+ previously stored and on the size of the inward Ca2+ current during the plateau of the action potential.

4. As a result of this Ca2+ release, intracellular [Ca2+] increases. 5. Ca2+ binds to troponin C, and tropomyosin is moved out of the way, removing the inhibition of actin and myosin binding. 6. Actin and myosin bind, the thick and thin filaments slide past each other, and the myocardial cell contracts. The magnitude of the tension that develops is proportional to the intracellular [Ca2+]. 7. Relaxation occurs when Ca2+ is reaccumulated by the SR by an active Ca2+-ATPase pump.

C. Contractility ■ ■ ■ ■ ■ ■

is the intrinsic ability of cardiac muscle to develop force at a given muscle length. is also called inotropism. is related to the intracellular Ca2+ concentration. can be estimated by the ejection fraction (stroke volume/end-diastolic volume), which is normally 0.55 (55%). Positive inotropic agents produce an increase in contractility. Negative inotropic agents produce a decrease in contractility.

1. Factors that increase contractility (positive inotropism) [see Table 3-1] a. Increased heart rate ■

■

When more action potentials occur per unit time, more Ca2+ enters the myocardial cells during the action potential plateaus, more Ca2+ is released from the SR, and greater tension is produced during contraction. Examples of the effect of increased heart rate are:

(1) Positive staircase, or Bowditch staircase (or Treppe). Increased heart rate increases the force of contraction in a stepwise fashion as the intracellular [Ca2+] increases cumulatively over several beats. (2) Postextrasystolic potentiation. The beat that occurs after an extrasystolic beat has increased force of contraction because “extra” Ca2+ entered the cells during the extrasystole.


76


Na+ 2

[Na+]

K+

1

Ca2+ 4

[Ca2+]

Myocardial cell

Na+

3 FIGURE 3-7 Stepwise explanation of how ouabain (digitalis) causes an increase in intracellular [Ca2+] and myocardial contractility. The circled numbers show the sequence of events.

b. Sympathetic stimulation (catecholamines) via a1 receptors (see Table 3-1) ■

increases the force of contraction by two mechanisms:

(1) It increases the inward Ca2+ current during the plateau of each cardiac action potential. (2) It increases the activity of the Ca2+ pump of the SR (by phosphorylation of phospholamban); as a result, more Ca2+ is accumulated by the SR and thus more Ca2+ is available for release in subsequent beats.

c. Cardiac glycosides (digitalis) ■ ■ ■

increase the force of contraction by inhibiting Na+,K+-ATPase in the myocardial cell membrane (Figure 3-7). As a result of this inhibition, the intracellular [Na+] increases, diminishing the Na+ gradient across the cell membrane. Na+–Ca2+ exchange (a mechanism that extrudes Ca2+ from the cell) depends on the size of the Na+ gradient and thus is diminished, producing an increase in intracellular [Ca2+].

2. Factors that decrease contractility (negative inotropism) [see Table 3-1] ■

Parasympathetic stimulation (ACh) via muscarinic receptors decreases the force of contraction in the atria by decreasing the inward Ca2+ current during the plateau of the cardiac action potential.

D. Length–tension relationship in the ventricles (Figure 3-8) ■ ■

describes the effect of ventricular muscle cell length on the force of contraction. is similar to the relationship in skeletal muscle.

1. Preload ■ ■

is end-diastolic volume, which is related to right atrial pressure. When venous return increases, end-diastolic volume increases and stretches or lengthens the ventricular muscle fibers (see Frank–Starling relationship, IV D 5).

2. Afterload ■ ■

for the left ventricle is aortic pressure. Increases in aortic pressure cause an increase in afterload on the left ventricle. for the right ventricle is pulmonary artery pressure. Increases in pulmonary artery pressure cause an increase in afterload on the right ventricle.

3. Sarcomere length ■ ■

determines the maximum number of cross-bridges that can form between actin and myosin. determines the maximum tension, or force of contraction.

4. Velocity of contraction at a fixed muscle length ■ ■

is maximal when the afterload is zero. is decreased by increases in afterload.


77


Positive inotropic effect

Stroke volume or cardiac output

Control

Negative inotropic effect

Right atrial pressure or end-diastolic volume FIGURE 3-8 Frank–Starling relationship and the effect of positive and negative inotropic agents.

5. Frank–Starling relationship ■ ■

■ ■

describes the increases in stroke volume and cardiac output that occur in response to an increase in venous return or end-diastolic volume (see Figure 3-8). is based on the length–tension relationship in the ventricle. Increases in end-diastolic volume cause an increase in ventricular fiber length, which produces an increase in developed tension. is the mechanism that matches cardiac output to venous return. The greater the venous return, the greater the cardiac output. Changes in contractility shift the Frank–Starling curve upward (increased contractility) or downward (decreased contractility).

a. Increases in contractility cause an increase in cardiac output for any level of right atrial pressure or end-diastolic volume.

b. Decreases in contractility cause a decrease in cardiac output for any level of right atrial pressure or end-diastolic volume.

E. Ventricular pressure–volume loops (Figure 3-9) ■

are constructed by combining systolic and diastolic pressure curves. The diastolic pressure curve is the relationship between diastolic pressure and diastolic volume in the ventricle.

Left ventricular pressure (mm Hg)

■

150 3 2

75

4

0 0 FIGURE 3-9 Left ventricular pressure–volume loop.

50 100 Left ventricular volume (mL)

1 150


78


The systolic pressure curve is the corresponding relationship between systolic pressure and systolic volume in the ventricle. A single left ventricular cycle of contraction, ejection, relaxation, and refilling can be visualized by combining the two curves into a pressure–volume loop.

1. Steps in the cycle a. 1 ã 2 (isovolumetric contraction). The cycle begins during diastole at point 1. The left ventricle is filled with blood from the left atrium and its volume is about 140 mL (end-diastolic volume). Ventricular pressure is low because the ventricular muscle is relaxed. On excitation, the ventricle contracts and ventricular pressure increases. The mitral valve closes when left ventricular pressure is greater than left atrial pressure. Because all valves are closed, no blood can be ejected from the ventricle (isovolumetric). b. 2 ã 3 (ventricular ejection). The aortic valve opens at point 2 when pressure in the left ventricle exceeds pressure in the aorta. Blood is ejected into the aorta, and ventricular volume decreases. The volume that is ejected in this phase is the stroke volume. Thus, stroke volume can be measured graphically by the width of the pressure– volume loop. The volume remaining in the left ventricle at point 3 is end-systolic volume. c. 3 ã 4 (isovolumetric relaxation). At point 3, the ventricle relaxes. When ventricular pressure decreases to less than aortic pressure, the aortic valve closes. Because all of the valves are closed again, ventricular volume is constant (isovolumetric) during this phase. d. 4 ã 1 (ventricular filling). Once left ventricular pressure decreases to less than left atrial pressure, the mitral (AV) valve opens and filling of the ventricle begins. During this phase, ventricular volume increases to about 140 mL (the end-diastolic volume). 2. Changes in the ventricular pressure–volume loop are caused by several factors (Figure 3-10). a. Increased preload (see Figure 3-10A) ■ ■ ■

refers to an increase in end-diastolic volume and is the result of increased venous return. causes an increase in stroke volume based on the Frank–Starling relationship. The increase in stroke volume is reflected in increased width of the pressure– volume loop.

b. Increased afterload (see Figure 3-10B) ■ ■ ■ ■

refers to an increase in aortic pressure. The ventricle must eject blood against a higher pressure, resulting in a decrease in stroke volume. The decrease in stroke volume is reflected in decreased width of the pressure–volume loop. The decrease in stroke volume results in an increase in end-systolic volume.

Left ventricular pressure

A

B

C

Increased preload 3

Increased afterload 3

3

2 4

1

Left ventricular volume

Increased contractility

2 4

1


2 4

1


FIGURE 3-10 Effects of changes in (A) preload, (B) afterload, and (C) contractility on the ventricular pressure–volume loop.



79

Cardiac output or venous return (L/min)

Cardiac output

Ve

no

us

re

tu

rn

Mean systemic pressure

Right atrial pressure (mm Hg) or end-diastolic volume (L) FIGURE 3-11 Simultaneous plots of the cardiac and vascular function curves. The curves cross at the equilibrium point for the cardiovascular system.

c. Increased contractility (see Figure 3-10C) ■ ■

The ventricle develops greater tension than usual during systole, causing an increase in stroke volume. The increase in stroke volume results in a decrease in end-systolic volume.

F. Cardiac and vascular function curves (Figure 3-11) ■

are simultaneous plots of cardiac output and venous return as a function of right atrial pressure or end-diastolic volume.

1. The cardiac function (cardiac output) curve ■ ■

depicts the Frank–Starling relationship for the ventricle. shows that cardiac output is a function of end-diastolic volume.

2. The vascular function (venous return) curve ■

depicts the relationship between blood flow through the vascular system (or venous return) and right atrial pressure.

a. Mean systemic pressure ■ ■ ■

is the point at which the vascular function curve intersects the x-axis. equals right atrial pressure when there is “no flow” in the cardiovascular system. is measured when the heart is stopped experimentally. Under these conditions, cardiac output and venous return are zero, and pressure is equal throughout the cardiovascular system.

(1) Mean systemic pressure is increased by an increase in blood volume or by a decrease in venous compliance (where blood is shifted from the veins to the arteries). An increase in mean systemic pressure is reflected in a shift of the vascular function curve to the right (Figure 3-12). (2) Mean systemic pressure is decreased by a decrease in blood volume or by an increase in venous compliance (where blood is shifted from the arteries to the veins). A decrease in mean systemic pressure is reflected in a shift of the vascular function curve to the left. b. Slope of the venous return curve ■

is determined by the resistance of the arterioles.


80



Cardiac output

Ve

Increased blood volume no

us

re

tu

rn


Right atrial pressure (mm Hg) or end-diastolic volume (L) FIGURE 3-12 Effect of increased blood volume on the mean systemic pressure, vascular function curve, cardiac output, and right atrial pressure.

(1) A clockwise rotation of the venous return curve indicates a decrease in total peripheral resistance (TPR). When TPR is decreased for a given right atrial pressure, there is an increase in venous return (i.e., vasodilation of the arterioles “allows” more blood to flow from the arteries to the veins and back to the heart). (2) A counterclockwise rotation of the venous return curve indicates an increase in TPR (Figure 3-13). When TPR is increased for a given right atrial pressure, there is a decrease in venous return to the heart (i.e., vasoconstriction of the arterioles decreases blood flow from the arteries to the veins and back to the heart).

3. Combining cardiac output and venous return curves ■ ■

When cardiac output and venous return are simultaneously plotted as a function of right atrial pressure, they intersect at a single value of right atrial pressure. The point at which the two curves intersect is the equilibrium, or steady-state, point (see Figure 3-11). Equilibrium occurs when cardiac output equals venous return.


Cardiac output

Ve

no

us

re

tu

Increased TPR

rn


Right atrial pressure (mm Hg) or end-diastolic volume (L) FIGURE 3-13 Effect of increased total peripheral resistance (TPR) on the cardiac and vascular function curves and on cardiac output.


Chapter 3 Cardiovascular Physiology ■

81

Cardiac output can be changed by altering the cardiac output curve, the venous return curve, or both curves simultaneously. The superimposed curves can be used to predict the direction and magnitude of changes in cardiac output.

a. Inotropic agents change the cardiac output curve. (1) Positive inotropic agents (e.g., digitalis) produce increased contractility and increased cardiac output (Figure 3-14). ■ ■

The equilibrium, or intersection, point shifts to a higher cardiac output and a correspondingly lower right atrial pressure. Right atrial pressure decreases because more blood is ejected from the heart on each beat (increased stroke volume).

(2) Negative inotropic agents produce decreased contractility and decreased cardiac output (not illustrated).

b. Changes in blood volume or venous compliance change the venous return curve. (1) Increases in blood volume or decreases in venous compliance increase mean systemic pressure, shifting the venous return curve to the right in a parallel fashion (see Figure 3-12). A new equilibrium, or intersection, point is established at which both cardiac output and right atrial pressure are increased. (2) Decreases in blood volume (e.g., hemorrhage) or increases in venous compliance have the opposite effect—decreased mean systemic pressure and a shift of the venous return curve to the left in a parallel fashion. A new equilibrium point is established at which both cardiac output and right atrial pressure are decreased

(not illustrated). c. Changes in TPR change both the cardiac output and the venous return curves. ■

Changes in TPR alter both curves simultaneously; therefore, the responses are more complicated than those noted in the previous examples.

(1) Increasing TPR causes a decrease in both cardiac output and venous return (see Figure 3-13).

(a) A counterclockwise rotation of the venous return curve occurs. Increased TPR results in decreased venous return as blood is retained on the arterial side.

(b) A downward shift of the cardiac output curve is caused by the increased aortic pressure (increased afterload) as the heart pumps against a higher pressure.

(c) As a result of these simultaneous changes, a new equilibrium point is established at which both cardiac output and venous return are decreased, but right atrial pressure is unchanged.


Positive inotropic effect Cardiac output

Ve

no

us

re

tu

rn


Right atrial pressure (mm Hg) or end-diastolic volume (L) FIGURE 3-14 Effect of a positive inotropic agent on the cardiac function curve, cardiac output, and right atrial pressure.


82


(2) Decreasing TPR causes an increase in both cardiac output and venous return (not illustrated).

(a) A clockwise rotation of the venous return curve occurs. Decreased TPR results in increased venous return as more blood is allowed to flow back to the heart from the arterial side. (b) An upward shift of the cardiac output curve is caused by the decreased aortic pressure (decreased afterload) as the heart pumps against a lower pressure. (c) As a result of these simultaneous changes, a new equilibrium point is established at which both cardiac output and venous return are increased, but right atrial pressure is unchanged.

G. Stroke volume, cardiac output, and ejection fraction 1. Stroke volume ■ ■

is the volume ejected from the ventricle on each beat. is expressed by the following equation: Stroke volume = End-diastolic volume − End-systolic volume

2. Cardiac output ■

is expressed by the following equation: Cardiac output = Stroke volume × Heart rate

3. Ejection fraction ■ ■ ■ ■

is the fraction of the end-diastolic volume ejected in each stroke volume. is related to contractility. is normally 0.55 or 55%. is expressed by the following equation: Ejection fraction =

Stroke volume End-diastolic volume

H. Stroke work ■ ■ ■

is the work the heart performs on each beat. is equal to pressure ë volume. For the left ventricle, pressure is aortic pressure and volume is stroke volume. is expressed by the following equation: Stroke work = Aortic pressure × Stroke volume

■

Fatty acids are the primary energy source for stroke work.

I. Cardiac oxygen (O2) consumption ■ ■

is directly related to the amount of tension developed by the ventricles. is increased by:

1. Increased afterload (increased aortic pressure) 2. Increased size of the heart (Laplace’s law states that tension is proportional to the radius of a sphere.)

3. Increased contractility 4. Increased heart rate



83

J. Measurement of cardiac output by the Fick principle ■

The Fick principle for measuring cardiac output is expressed by the following equation: Cardiac output =

■

O2 consumption ⎡⎣O2 ⎤⎦ − ⎡⎣O2 ⎤⎦pulmonary artery pulmonary vein

The equation is solved as follows:

1. O2 consumption for the whole body is measured. 2. Pulmonary vein [O2] is measured in a peripheral artery. 3. Pulmonary artery [O2] is measured in systemic mixed venous blood. ■

For example, a 70-kg man has a resting O2 consumption of 250 mL/min, a peripheral arterial O2 content of 0.20 mL O2/mL of blood, a mixed venous O2 content of 0.15 mL O2/mL of blood, and a heart rate of 72 beats/min. What is his cardiac output? What is his stroke volume? Cardiac output =

250 mL min 0.20 mL O2 mL − 0.15 mL O2 mL

= 5000 mL min, or 5.0 L min Stroke volume = =

Cardiac output Heart rate 5000 mL miin 72 beats min

= 69.4 mL beat

V. CARDIAC CYCLE ■ ■ ■ ■

Figure 3-15 shows the mechanical and electrical events of a single cardiac cycle. The seven phases are separated by vertical lines. Use the ECG as an event marker. Opening and closing of valves causes the physiologic heart sounds. When all valves are closed, ventricular volume is constant, and the phase is called isovolumetric.

A. Atrial systole ■ ■ ■ ■

is preceded by the P wave, which represents electrical activation of the atria. contributes to, but is not essential for, ventricular filling. The increase in atrial pressure (venous pressure) caused by atrial systole is the a wave on the venous pulse curve. Filling of the ventricle by atrial systole causes the fourth heart sound, which is not audible in normal adults.

B. Isovolumetric ventricular contraction ■ ■

begins after the onset of the QRS wave, which represents electrical activation of the ventricles. When ventricular pressure becomes greater than atrial pressure, the AV valves close. Their closure corresponds to the first heart sound. Because the mitral valve closes before the tricuspid valve, the first heart sound may be split.


84


A

B C

D

E

120

G

Aortic valve closes

100 Pressure (mm Hg)

F

Aortic pressure

Aortic valve opens

80

Left ventricular pressure

60 40 Mitral valve closes Left atrial pressure

20

Mitral valve opens

0

1

2

4

3

Heart sounds

Ventricular volume

c a v Venous pulse R T

P

ECG

P

Q S

0

0.1

0.2

0.3

0.4

0.5

Time (sec)

0.6

0.7

0.8

FIGURE 3-15 The cardiac cycle. ECG = electrocardiogram; A = atrial systole; B = isovolumetric ventricular contraction; C = rapid ventricular ejection; D = reduced ventricular ejection; E = isovolumetric ventricular relaxation; F = rapid ventricular filling; G = reduced ventricular filling.


Chapter 3 Cardiovascular Physiology ■

85

Ventricular pressure increases isovolumetrically as a result of ventricular contraction. However, no blood leaves the ventricle during this phase because the aortic valve is closed.

C. Rapid ventricular ejection ■ ■ ■ ■ ■ ■

Ventricular pressure reaches its maximum value during this phase. When ventricular pressure becomes greater than aortic pressure, the aortic valve opens. Rapid ejection of blood into the aorta occurs because of the pressure gradient between the ventricle and the aorta. Ventricular volume decreases dramatically because most of the stroke volume is ejected during this phase. Atrial filling begins. The onset of the T wave, which represents repolarization of the ventricles, marks the end of both ventricular contraction and rapid ventricular ejection.

D. Reduced ventricular ejection ■ ■ ■ ■

Ejection of blood from the ventricle continues, but is slower. Ventricular pressure begins to decrease. Aortic pressure also decreases because of the runoff of blood from large arteries into smaller arteries. Atrial filling continues.

E. Isovolumetric ventricular relaxation ■ ■

■ ■ ■ ■ ■

Repolarization of the ventricles is now complete (end of the T wave). The aortic valve closes, followed by closure of the pulmonic valve. Closure of the semilunar valves corresponds to the second heart sound. Inspiration causes splitting of the second heart sound. The AV valves remain closed during most of this phase. Ventricular pressure decreases rapidly because the ventricle is now relaxed. Ventricular volume is constant (isovolumetric) because all of the valves are closed. The “blip” in the aortic pressure tracing occurs after closure of the aortic valve and is called the dicrotic notch, or incisura. When ventricular pressure becomes less than atrial pressure, the mitral valve opens.

F. Rapid ventricular filling ■ ■ ■

The mitral valve is open and ventricular filling from the atrium begins. Aortic pressure continues to decrease because blood continues to run off into the smaller arteries. Rapid flow of blood from the atria into the ventricles causes the third heart sound, which is normal in children but, in adults, is associated with disease.

G. Reduced ventricular filling (diastasis) ■ ■ ■

is the longest phase of the cardiac cycle. Ventricular filling continues, but at a slower rate. The time required for diastasis and ventricular filling depends on heart rate. Increases in heart rate decrease the time available for ventricular refilling.

VI. REGULATION OF ARTERIAL PRESSURE ■

The most important mechanisms for regulating arterial pressure are a fast, neurally mediated baroreceptor mechanism and a slower, hormonally regulated renin– angiotensin–aldosterone mechanism.


86


A. Baroreceptor reflex ■ ■ ■

includes fast, neural mechanisms. is a negative feedback system that is responsible for the minute-to-minute regulation of arterial blood pressure. Baroreceptors are stretch receptors located within the walls of the carotid sinus near the bifurcation of the common carotid arteries.

1. Steps in the baroreceptor reflex (Figure 3-16)

a. A decrease in arterial pressure decreases stretch on the walls of the carotid sinus. ■ ■

Because the baroreceptors are most sensitive to changes in arterial pressure, rapidly decreasing arterial pressure produces the greatest response. Additional baroreceptors in the aortic arch respond to increases, but not to decreases, in arterial pressure.

b. Decreased stretch decreases the firing rate of the carotid sinus nerve [Hering’s nerve, cranial nerve (CN) IX], which carries information to the vasomotor center in the brain stem.

c. The set point for mean arterial pressure in the vasomotor center is about 100 mm Hg. Therefore, if mean arterial pressure is less than 100 mm Hg, a series of autonomic

Acute hemorrhage

Pa

Stretch on carotid sinus baroreceptors

Firing rate of carotid sinus nerve (Hering's nerve)

Parasympathetic outflow to heart

Sympathetic outflow to heart and blood vessels

Heart rate

Heart rate Contractility Constriction of arterioles (

TPR)

Constriction of veins Unstressed volume Venous return Mean systemic pressure

Pa toward normal FIGURE 3-16 Role of the baroreceptor reflex in the cardiovascular response to hemorrhage. Pa = mean arterial pressure; TPR = total peripheral resistance.



87

responses is coordinated by the vasomotor center. These changes will attempt to increase blood pressure toward normal. d. The responses of the vasomotor center to a decrease in mean arterial blood pressure are coordinated to increase the arterial pressure to 100 mm Hg. The responses are

decreased parasympathetic (vagal) outflow to the heart and increased sympathetic outflow to the heart and blood vessels. ■

The following four effects attempt to increase the arterial pressure to normal:

(1) ↑ heart rate, resulting from decreased parasympathetic tone and increased sympathetic tone to the SA node of the heart.

(2) ↑ contractility and stroke volume, resulting from increased sympathetic tone to the heart. Together with the increase in heart rate, the increases in contractility and stroke volume produce an increase in cardiac output that increases arterial pressure. (3) ↑ vasoconstriction of arterioles, resulting from the increased sympathetic outflow. As a result, TPR and arterial pressure will increase. (4) ↑ vasoconstriction of veins (venoconstriction), resulting from the increased sympathetic outflow. Constriction of the veins causes a decrease in unstressed volume and an increase in venous return to the heart. The increase in venous return causes an increase in cardiac output by the Frank–Starling mechanism.

2. Example of the baroreceptor reflex: response to acute blood loss (see Figure 3-16) 3. Example of the baroreceptor mechanism: Valsalva maneuver ■ ■ ■ ■

■

The integrity of the baroreceptor mechanism can be tested with the Valsalva maneuver (i.e., expiring against a closed glottis). Expiring against a closed glottis causes an increase in intrathoracic pressure, which decreases venous return. The decrease in venous return causes a decrease in cardiac output and arterial pressure (Pa). If the baroreceptor reflex is intact, the decrease in Pa is sensed by the baroreceptors, leading to an increase in sympathetic outflow to the heart and blood vessels. In the test, an increase in heart rate would be noted. When the person stops the maneuver, there is a rebound increase in venous return, cardiac output, and Pa. The increase in Pa is sensed by the baroreceptors, which direct a decrease in heart rate.

B. Renin–angiotensin–aldosterone system ■ ■ ■ ■ ■ ■

is a slow, hormonal mechanism. is used in long-term blood pressure regulation by adjustment of blood volume. Renin is an enzyme. Angiotensin I is inactive. Angiotensin II is physiologically active. Angiotensin II is degraded by angiotensinase. One of the peptide fragments, angiotensin III, has some of the biologic activity of angiotensin II.

1. Steps in the renin–angiotensin–aldosterone system (Figure 3-17) a. A decrease in renal perfusion pressure causes the juxtaglomerular cells of the afferent arteriole to secrete renin.

b. Renin is an enzyme that catalyzes the conversion of angiotensinogen to angiotensin I in plasma.

c. Angiotensin-converting enzyme (ACE) catalyzes the conversion of angiotensin I to angiotensin II, primarily in the lungs. ■ ■

ACE inhibitors (e.g., captopril) block the conversion of angiotensin I to angiotensin II and, therefore, decrease blood pressure. Angiotensin receptor (AT1) antagonists (e.g., losartan) block the action of angiotensin II at its receptor and decrease blood pressure.


88


Acute hemorrhage

Pa

Renal perfusion pressure

Renin Conversion of angiotensinogen to angiotensin I Angiotensin-converting enzyme (ACE) Conversion of angiotensin I to angiotensin II

Angiotensin II

Aldosterone Na+ reabsorption

Na+–H+ exchange

Na+ reabsorption

Thirst

Vasoconstriction

TPR

Pa toward normal FIGURE 3-17 Role of the renin–angiotensin–aldosterone system in the cardiovascular response to hemorrhage. Pa = mean arterial pressure; TPR = total peripheral resistance.

d. Angiotensin II has four effects: (1) It stimulates the synthesis and secretion of aldosterone by the adrenal cortex. ■ ■

Aldosterone increases Na+ reabsorption by the renal distal tubule, thereby increasing extracellular fluid (ECF) volume, blood volume, and arterial pressure. This action of aldosterone is slow because it requires new protein synthesis.

(2) It increases Na+–H+ exchange in the proximal convoluted tubule. ■ ■

This action of angiotensin II directly increases Na+ reabsorption, complementing the indirect stimulation of Na+ reabsorption via aldosterone. This action of angiotensin II leads to contraction alkalosis.

(3) It increases thirst. (4) It causes vasoconstriction of the arterioles, thereby increasing TPR and arterial pressure. 2. Example: response of the renin–angiotensin–aldosterone system to acute blood loss (see Figure 3-17)



89

C. Other regulation of arterial blood pressure 1. Cerebral ischemia a. When the brain is ischemic, the partial pressure of carbon dioxide (PCO2) in brain tissue increases.

b. Chemoreceptors in the vasomotor center respond by increasing sympathetic outflow to the heart and blood vessels. ■

■

Constriction of arterioles causes intense peripheral vasoconstriction and increased TPR. Blood flow to other organs (e.g., kidneys) is significantly reduced in an attempt to preserve blood flow to the brain. Mean arterial pressure can increase to life-threatening levels.

c. The Cushing reaction is an example of the response to cerebral ischemia. Increases in intracranial pressure cause compression of the cerebral blood vessels, leading to cerebral ischemia and increased cerebral PCO2. The vasomotor center directs an increase in sympathetic outflow to the heart and blood vessels, which causes a profound increase in arterial pressure.

2. Chemoreceptors in the carotid and aortic bodies ■ ■ ■

are located near the bifurcation of the common carotid arteries and along the aortic arch. have very high rates of O2 consumption and are very sensitive to decreases in the partial pressure of oxygen (PO2). Decreases in PO2 activate vasomotor centers that produce vasoconstriction, an increase in TPR, and an increase in arterial pressure.

3. Vasopressin [antidiuretic hormone (ADH)] ■ ■ ■

is involved in the regulation of blood pressure in response to hemorrhage, but not in minute-to-minute regulation of normal blood pressure. Atrial receptors respond to a decrease in blood volume (or blood pressure) and cause the release of vasopressin from the posterior pituitary. Vasopressin has two effects that tend to increase blood pressure toward normal:

a. It is a potent vasoconstrictor that increases TPR by activating V1 receptors on the arterioles.

b. It increases water reabsorption by the renal distal tubule and collecting ducts by activating V2 receptors. 4. Atrial natriuretic peptide (ANP) ■ ■ ■ ■

is released from the atria in response to an increase in blood volume and atrial pressure. causes relaxation of vascular smooth muscle, dilation of the arterioles, and decreased TPR. causes increased excretion of Na+ and water by the kidney, which reduces blood volume and attempts to bring arterial pressure down to normal. inhibits renin secretion.

VII. MICROCIRCULATION AND LYMPH A. Structure of capillary beds ■ ■

Metarterioles branch into the capillary beds. At the junction of the arterioles and capillaries is a smooth muscle band called the precapillary sphincter. True capillaries do not have smooth muscle; they consist of a single layer of endothelial cells surrounded by a basement membrane. ■

Clefts (pores) between the endothelial cells allow passage of water-soluble substances. The clefts represent a very small fraction of the surface area ( arterial pressure > venous pressure. The high alveolar pressure may compress the capillaries and reduce blood flow in zone. 1. This situation can occur if arterial blood pressure is decreased as a result of hemorrhage or if alveolar pressure is increased because of positive pressure ventilation.

2. Zone 2—blood flow is medium. ■ ■ ■

Arterial pressure > alveolar pressure > venous pressure. Moving down the lung, arterial pressure progressively increases because of gravitational effects on hydrostatic pressure. Arterial pressure is greater than alveolar pressure in zone 2, and blood flow is driven by the difference between arterial pressure and alveolar pressure.

3. Zone 3—blood flow is highest. ■ ■

■

Arterial pressure > venous pressure > alveolar pressure. Moving down toward the base of the lung, arterial pressure is highest because of gravitational effects, and venous pressure finally increases to the point where it exceeds alveolar pressure. In zone 3, blood flow is driven by the difference between arterial and venous pressures, as in most vascular beds.

C. Regulation of pulmonary blood flow—hypoxic vasoconstriction ■ ■ ■ ■

In the lungs, hypoxia causes vasoconstriction. This response is the opposite of that in other organs, where hypoxia causes vasodilation. Physiologically, this effect is important because local vasoconstriction redirects blood away from poorly ventilated, hypoxic regions of the lung and toward well-ventilated regions. Fetal pulmonary vascular resistance is very high because of generalized hypoxic vasoconstriction; as a result, blood flow through the fetal lungs is low. With the first breath, the alveoli of the neonate are oxygenated, pulmonary vascular resistance decreases, and pulmonary blood flow increases and becomes equal to cardiac output (as occurs in the adult).

D. Shunts 1. Right-to-left shunts ■ ■ ■ ■ ■

normally occur to a small extent because 2% of the cardiac output bypasses the lungs. may be as great as 50% of cardiac output in certain congenital abnormalities. are seen in tetralogy of Fallot. always result in a decrease in arterial PO2 because of the admixture of venous blood with arterial blood. The magnitude of a right-to-left shunt can be estimated by having the patient breathe 100% O2 and measuring the degree of dilution of oxygenated arterial blood by nonoxygenated shunted (venous) blood.

2. Left-to-right shunts ■

are more common than right-to-left shunts because pressures are higher on the left side of the heart.


Chapter 4 Respiratory Physiology

Q

V

V/Q

131

PO2 PcO2

Apex Zone 1

Zone 2

FIGURE 4-11 Regional variations in the lung of perfusion (blood flow [Q]), ventilation (V), V/Q, PO2, and PCO2.

■ ■

Zone 3 Base

are usually caused by congenital abnormalities (e.g., patent ductus arteriosus) or traumatic injury. do not result in a decrease in arterial PO2. Instead, PO2 will be elevated on the right side of the heart because there has been admixture of arterial blood with venous blood.

VII. V/Q DEFECTS A. V/Q ratio ■ ■

is the ratio of alveolar ventilation (V) to pulmonary blood flow (Q). Ventilation and perfusion matching is important to achieve the ideal exchange of O2 and CO2. If the frequency, tidal volume, and cardiac output are normal, the V/Q ratio is approximately 0.8. This V/Q ratio results in an arterial PO2 of 100 mm Hg and an arterial PCO2 of 40 mm Hg.

B. V/Q ratios in different parts of the lung (Figure 4-11 and Table 4-6) ■

Both ventilation and blood flow (perfusion) are nonuniformly distributed in the normal upright lung.

1. Blood flow is lowest at the apex and highest at the base because of gravitational effects. 2. Ventilation is lower at the apex and higher at the base, but the regional differences for ventilation are not as great as for perfusion.

3. Therefore, the V/Q ratio is higher at the apex of the lung and lower at the base of the lung. 4. As a result of the regional differences in V/Q ratio, there are corresponding differences in the efficiency of gas exchange and in the resulting pulmonary capillary PO2 and PCO2. Regional differences for PO2 are greater than those for PCO2. a. At the apex (higher V/Q), PO2 is highest and PCO2 is lower because gas exchange is more efficient. b. At the base (lower V/Q), PO2 is lowest and PCO2 is higher because gas exchange is less efficient.

C. Changes in V/Q ratio (Figure 4-12) 1. V/Q ratio in airway obstruction ■

If the airways are completely blocked (e.g., by a piece of steak caught in the trachea), then ventilation is zero. If blood flow is normal, then V/Q is zero, which is called a shunt.


132


4-6

V/Q Characteristics of Different Areas of the Lung

Area of Lung

Blood Flow

Ventilation

V/Q

Regional Arterial PO2

Regional Arterial PCO2

Apex Base

Lowest Highest

Lower Higher

Higher Lower

Highest Lowest

Lower Higher

V/Q = ventilation/perfusion ratio.

■

■

There is no gas exchange in a lung that is perfused but not ventilated. The PO2 and PCO2 of pulmonary capillary blood (and, therefore, of systemic arterial blood) will approach their values in mixed venous blood. There is an increased A–a gradient.

2. V/Q ratio in pulmonary embolism ■

■

If blood flow to a lung is completely blocked (e.g., by an embolism occluding a pulmonary artery), then blood flow to that lung is zero. If ventilation is normal, then V/Q is infinite, which is called dead space. There is no gas exchange in a lung that is ventilated but not perfused. The PO2 and PCO2 of alveolar gas will approach their values in inspired air.

VIII. CONTROL OF BREATHING ■ ■

Sensory information (PCO2, lung stretch, irritants, muscle spindles, tendons, and joints) is coordinated in the brain stem. The output of the brain stem controls the respiratory muscles and the breathing cycle.

V/Q DEFECTS Normal

V/Q

0.8

Airway obstruction (shunt)

Pulmonary embolus (dead space)

0

∞

PAO2

100 mm Hg

–

150 mm Hg

PACO2

40 mm Hg

–

0 mm Hg

PaO2

100 mm Hg

40 mm Hg

–

PaCO2

40 mm Hg

46 mm Hg

–

FIGURE 4-12 Effect of ventilation/perfusion (V/Q) defects on gas exchange. With airway obstruction, the composition of systemic arterial blood approaches that of mixed venous blood. With pulmonary embolus, the composition of alveolar gas approaches that of inspired air. PAO2 = alveolar PO2; PACO2 = alveolar PCO2; PaO2 = arterial PO2; PaCO2 = arterial PCO2.


Chapter 4 Respiratory Physiology

133

A. Central control of breathing (brain stem and cerebral cortex) 1. Medullary respiratory center ■

is located in the reticular formation.

a. Dorsal respiratory group ■ ■

■

is primarily responsible for inspiration and generates the basic rhythm for breathing. Input to the dorsal respiratory group comes from the vagus and glossopharyngeal nerves. The vagus nerve relays information from peripheral chemoreceptors and mechanoreceptors in the lung. The glossopharyngeal nerve relays information from peripheral chemoreceptors. Output from the dorsal respiratory group travels, via the phrenic nerve, to the diaphragm.

b. Ventral respiratory group ■ ■ ■

is primarily responsible for expiration. is not active during normal, quiet breathing, when expiration is passive. is activated, for example, during exercise, when expiration becomes an active process.

2. Apneustic center ■ ■

is located in the lower pons. stimulates inspiration, producing a deep and prolonged inspiratory gasp (apneusis).

3. Pneumotaxic center ■ ■

is located in the upper pons. inhibits inspiration and, therefore, regulates inspiratory volume and respiratory rate.

4. Cerebral cortex ■ ■

Breathing can be under voluntary control; therefore, a person can voluntarily hyperventilate or hypoventilate. Hypoventilation (breath-holding) is limited by the resulting increase in PCO2 and decrease in PO2. A previous period of hyperventilation extends the period of breathholding.

B. Chemoreceptors for CO2, H+, and O2 (Table 4-7) 1. Central chemoreceptors in the medulla ■ ■

are sensitive to the pH of the cerebrospinal fluid (CSF). Decreases in the pH of the CSF produce increases in breathing rate (hyperventilation). H+ does not cross the blood–brain barrier as well as CO2 does.

a. CO2 diffuses from arterial blood into the CSF because CO2 is lipid-soluble and readily crosses the blood–brain barrier.

t a b l e

4-7

Comparison of Central and Peripheral Chemoreceptors

Type of Chemoreceptor

Location

Stimuli that Increase Breathing Rate

Central

Medulla

Peripheral

Carotid and aortic bodies

↓ pH ↑ (PCO2) ↓ PO2 (if < 60 mm Hg) ↑ PCO2 ↓ pH


134


b. In the CSF, CO2 combines with H2O to produce H+ and HCO3–. The resulting H+ acts directly on the central chemoreceptors.

c. Thus, increases in PCO2 and [H+] stimulate breathing, and decreases in PCO2 and [H+] inhibit breathing.

d. The resulting hyperventilation or hypoventilation then returns the arterial PCO2 toward normal.

2. Peripheral chemoreceptors in the carotid and aortic bodies ■ ■

The carotid bodies are located at the bifurcation of the common carotid arteries. The aortic bodies are located above and below the aortic arch.

a. Decreases in arterial PO2 ■ ■

stimulate the peripheral chemoreceptors and increase breathing rate. PO2 must decrease to low levels ( K+ (high-K+ diet) > inulin > urea > Na+ > glucose, amino acids, and HCO3−.

E. Nonionic diffusion 1. Weak acids ■ ■ ■ ■ ■

have an HA form and an A− form. The HA form, which is uncharged and lipid-soluble, can “back-diffuse” from urine to blood. The A– form, which is charged and not lipid-soluble, cannot back-diffuse. At acidic urine pH, the HA form predominates, there is more back-diffusion, and there is decreased excretion of the weak acid. At alkaline urine pH, the A– form predominates, there is less back-diffusion, and there is increased excretion of the weak acid. For example, the excretion of salicylic acid can be increased by alkalinizing the urine.

2. Weak bases ■ ■ ■ ■ ■

have a BH+ form and a B form. The B form, which is uncharged and lipid-soluble, can “back-diffuse” from urine to blood. The BH+ form, which is charged and not lipid-soluble, cannot back-diffuse. At acidic urine pH, the BH+ form predominates, there is less back-diffusion, and there is increased excretion of the weak base. At alkaline urine pH, the B form predominates, there is more back-diffusion, and there is decreased excretion of the weak base.

IV. NaCl REGULATION A. Single nephron terminology ■ ■

Tubular fluid (TF) is urine at any point along the nephron. Plasma (P) is systemic plasma. It is considered to be constant.

1. TF/Px ratio ■

compares the concentration of a substance in tubular fluid at any point along the nephron with the concentration in plasma.

a. If TF/P = 1.0, then either there has been no reabsorption of the substance or reabsorption of the substance has been exactly proportional to the reabsorption of water. ■ ■

For example, if TF/PNa+ = 1.0, the [Na+] in tubular fluid is identical to the [Na+] in plasma. For any freely filtered substance, TF/P = 1.0 in Bowman’s space (before any reabsorption or secretion has taken place to modify the tubular fluid).

b. If TF/P < 1.0, then reabsorption of the substance has been greater than the reabsorption of water and the concentration in tubular fluid is less than that in plasma. ■

For example, if TF/PNa+ = 0.8, then the [Na+] in tubular fluid is 80% of the [Na+] in plasma.

c. If TF/P > 1.0, then either reabsorption of the substance has been less than the reabsorption of water or there has been secretion of the substance.


156


2. TF/Pinulin ■ ■ ■ ■

is used as a marker for water reabsorption along the nephron. increases as water is reabsorbed. Because inulin is freely filtered, but not reabsorbed or secreted, its concentration in tubular fluid is determined solely by how much water remains in the tubular fluid. The following equation shows how to calculate the fraction of the filtered water that has been reabsorbed: Fraction of filtered H2O reabsorbed = 1 −

■

1 ⎡⎣ TF P ⎤⎦inulin

For example, if 50% of the filtered water has been reabsorbed, the TF/Pinulin = 2.0. For another example, if TF/Pinulin = 3.0, then 67% of the filtered water has been reabsorbed (i.e., 1−1/3).

3. [TF/P]x /[TF/P]inulin ratio ■ ■

corrects the TF/Px ratio for water reabsorption. This double ratio gives the fraction of the filtered load remaining at any point along the nephron. For example, if [TF/P]K+/[TF/P]inulin = 0.3 at the end of the proximal tubule, then 30% of the filtered K+ remains in the tubular fluid and 70% has been reabsorbed into the blood.

B. General information about Na+ reabsorption ■ ■

Na+ is freely filtered across the glomerular capillaries; therefore, the [Na+] in the tubular fluid of Bowman’s space equals that in plasma (i.e., TF/PNa+ = 1.0). Na+ is reabsorbed along the entire nephron, and very little is excreted in urine ( blood osmolarity. is produced when circulating ADH levels are high (e.g., water deprivation, hemorrhage, SIADH).

1. Corticopapillary osmotic gradient—high ADH ■ ■ ■

is the gradient of osmolarity from the cortex (300 mOsm/L) to the papilla (1200 mOsm/L), and is composed primarily of NaCl and urea. is established by countercurrent multiplication and urea recycling. is maintained by countercurrent exchange in the vasa recta.


164


Water deprivation

Increases plasma osmolarity

Stimulates osmoreceptors in anterior hypothalamus

Increases secretion of ADH from posterior pituitary

Increases water permeability of late distal tubule and collecting duct

Increases water reabsorption

Increases urine osmolarity and decreases urine volume

Decreases plasma osmolarity toward normal FIGURE 5-14 Responses to water deprivation. ADH = antidiuretic hormone.

a. Countercurrent multiplication in the loop of Henle depends on NaCl reabsorption in the thick ascending limb and countercurrent flow in the descending and ascending limbs of the loop of Henle. ■ is augmented by ADH, which stimulates NaCl reabsorption in the thick ascending limb. Therefore, the presence of ADH increases the size of the corticopapillary osmotic gradient. b. Urea recycling from the inner medullary collecting ducts into the medullary interstitial fluid also is augmented by ADH. c. Vasa recta are the capillaries that supply the loop of Henle. They maintain the corticopapillary gradient by serving as osmotic exchangers. Vasa recta blood equilibrates osmotically with the interstitial fluid of the medulla and papilla. ■

2. Proximal tubule—high ADH ■ ■ ■

The osmolarity of the glomerular filtrate is identical to that of plasma (300 mOsm/L). Two-thirds of the filtered H2O is reabsorbed isosmotically (with Na+, Cl–, HCO3–, glucose, amino acids, and so forth) in the proximal tubule. TF/Posm = 1.0 throughout the proximal tubule because H2O is reabsorbed isosmotically with solute.

3. Thick ascending limb of the loop of Henle—high ADH ■ ■

is called the diluting segment. reabsorbs NaCl by the Na+–K+–2Cl– cotransporter.


Chapter 5 Renal and Acid–Base Physiology

165

Water intake

Decreases plasma osmolarity

Inhibits osmoreceptors in anterior hypothalamus

Decreases secretion of ADH from posterior pituitary

Decreases water permeability of late distal tubule and collecting duct

Decreases water reabsorption

Decreases urine osmolarity and increases urine volume

Increases plasma osmolarity toward normal FIGURE 5-15 Responses to water intake. ADH = antidiuretic hormone.

300

300 300 300 100

600

FIGURE 5-16 Mechanisms for producing hyperosmotic (concentrated) urine in the presence of antidiuretic hormone (ADH). Numbers indicate osmolarity. Heavy arrows indicate water reabsorption. The thick outline shows the water-impermeable segments of the nephron. (Adapted with permission from Valtin H. Renal Function. 3rd ed. Boston: Little, Brown; 1995:158.)

1200

1200

High ADH


166


is impermeable to H2O. Therefore, H2O is not reabsorbed with NaCl, and the tubular fluid becomes dilute. The fluid that leaves the thick ascending limb has an osmolarity of 100 mOsm/L and TF/Posm < 1.0 as a result of the dilution process.

4. Early distal tubule—high ADH ■ ■

is called the cortical diluting segment. Like the thick ascending limb, the early distal tubule reabsorbs NaCl but is impermeable to water. Consequently, tubular fluid is further diluted.

5. Late distal tubule—high ADH ■ ■ ■

ADH increases the H2O permeability of the principal cells of the late distal tubule. H2O is reabsorbed from the tubule until the osmolarity of distal tubular fluid equals that of the surrounding interstitial fluid in the renal cortex (300 mOsm/L). TF/Posm = 1.0 at the end of the distal tubule because osmotic equilibration occurs in the presence of ADH.

6. Collecting ducts—high ADH ■ ■

■ ■ ■

As in the late distal tubule, ADH increases the H2O permeability of the principal cells of the collecting ducts. As tubular fluid flows through the collecting ducts, it passes through the corticopapillary gradient (regions of increasingly higher osmolarity), which was previously established by countercurrent multiplication and urea recycling. H2O is reabsorbed from the collecting ducts until the osmolarity of tubular fluid equals that of the surrounding interstitial fluid. The osmolarity of the final urine equals that at the bend of the loop of Henle (1200 mOsm/L). TF/Posm > 1.0 because osmotic equilibration occurs with the corticopapillary gradient in the presence of ADH.

C. Production of dilute urine (Figure 5-17) ■ ■

is called hyposmotic urine, in which urine osmolarity < blood osmolarity. is produced when circulating levels of ADH are low (e.g., water intake, central diabetes insipidus) or when ADH is ineffective (nephrogenic diabetes insipidus).

100

300 300

No ADH

300 120

450

600

50

FIGURE 5-17 Mechanisms for producing hyposmotic (dilute) urine in the absence of antidiuretic hormone (ADH). Numbers indicate osmolarity. Heavy arrow indicates water reabsorption. The thick outline shows the water-impermeable segments of the nephron. (Adapted with permission from Valtin H. Renal Function. 3rd ed. Boston: Little, Brown; 1995:159.)



167

1. Corticopapillary osmotic gradient—no ADH ■

is smaller than in the presence of ADH because ADH stimulates both countercurrent multiplication and urea recycling.

2. Proximal tubule—no ADH ■ ■

As in the presence of ADH, two-thirds of the filtered water is reabsorbed isosmotically. TF/Posm = 1.0 throughout the proximal tubule.

3. Thick ascending limb of the loop of Henle—no ADH ■ ■

As in the presence of ADH, NaCl is reabsorbed without water, and the tubular fluid becomes dilute (although not quite as dilute as in the presence of ADH). TF/Posm < 1.0.

4. Early distal tubule—no ADH ■

As in the presence of ADH, NaCl is reabsorbed without H2O and the tubular fluid is further diluted.

■

TF/Posm < 1.0.

5. Late distal tubule and collecting ducts—no ADH ■ ■ ■ ■

In the absence of ADH, the cells of the late distal tubule and collecting ducts are impermeable to H2O. Thus, even though the tubular fluid flows through the corticopapillary osmotic gradient, osmotic equilibration does not occur. The osmolarity of the final urine will be dilute with an osmolarity as low as 50 mOsm/L. TF/Posm < 1.0.

D. Free-water clearance (CH O) 2

■ ■

■ ■

is used to estimate the ability to concentrate or dilute the urine. Free water, or solute-free water, is produced in the diluting segments of the kidney (i.e., thick ascending limb and early distal tubule), where NaCl is reabsorbed and free water is left behind in the tubular fluid. In the absence of ADH, this solute-free water is excreted and CH2O is positive. In the presence of ADH, this solute-free water is not excreted, but is reabsorbed by the late distal tubule and collecting ducts, and CH2O is negative.

1. Calculation of CH

2O

CH O ⴝ V ⴚ Cosm 2

where: CH2O = free-water clearance (mL/min) V = urine flow rate (mL/min) Cosm = osmolar clearance (Uosm V/Posm) [mL/min] ■

Example: If the urine flow rate is 10 mL/min, urine osmolarity is 100 mOsm/L, and plasma osmolarity is 300 mOsm/L, what is the free-water clearance? CH O = V − Cosm 2

100 mOsm L × 10 mL min 300 mOsm L = 10 mL min − 3.33 mL min = +6.7 mL min = 10 mL min −


168


t a b l e

5-6

Summary of ADH Pathophysiology Serum Osmolarity/ Serum [Na+]

Serum ADH

Urine Osmolarity

Urine Flow Rate

CH2O

Primary polydipsia Central diabetes insipidus

↓ ↓

Decreased Increased (because of excretion of too much H2O)

Hyposmotic Hyposmotic

High High

Positive Positive

Nephrogenic diabetes insipidus

↑ (because of increased plasma osmolarity)

Increased (because of excretion of too much H2O)

Hyposmotic

High

Positive

Water deprivation SIADH

↑ ↑↑

High–normal Decreased (because of reabsorption of too much H2O)

Hyperosmotic Hyperosmotic

Low Low

Negative Negative

ADH = antidiuretic hormone; CH2O = free-water clearance; SIADH = syndrome of inappropriate antidiuretic hormone.

2. Urine that is isosmotic to plasma (isosthenuric) ■ ■

CH2O is zero. is produced during treatment with a loop diuretic, which inhibits NaCl reabsorption in the thick ascending limb, inhibiting both dilution in the thick ascending limb and production of the corticopapillary osmotic gradient. Therefore, the urine cannot be diluted during high water intake (because a diluting segment is inhibited) or concentrated during water deprivation (because the corticopapillary gradient has been abolished).

3. Urine that is hyposmotic to plasma (low ADH) ■ ■

CH2O is positive. is produced with high water intake (in which ADH release from the posterior pituitary is suppressed), central diabetes insipidus (in which pituitary ADH is insufficient), or nephrogenic diabetes insipidus (in which the collecting ducts are unresponsive to ADH).

4. Urine that is hyperosmotic to plasma (high ADH) ■ ■

CH2O is negative. is produced in water deprivation (ADH release from the pituitary is stimulated) or SIADH.

E. Clinical disorders related to the concentration or dilution of urine (Table 5-6)

VIII. RENAL HORMONES ■

See Table 5-7 for a summary of renal hormones (see Chapter 7 for a discussion of hormones).

IX. ACID–BASE BALANCE A. Acid production ■

Two types of acid are produced in the body: volatile acid and nonvolatile acids.

1. Volatile acid ■ ■ ■

is CO2. is produced from the aerobic metabolism of cells. CO2 combines with H2O to form the weak acid H2CO3, which dissociates into H+ and HCO3– by the following reactions: CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3 −


Chapter 5 Renal and Acid–Base Physiology t a b l e

5-7

169

Summary of Hormones That Act on the Kidney

Hormone

Stimulus for Secretion

Time Course

Mechanism of Action

Actions on Kidneys

PTH

↓ plasma [Ca2+]

Fast

Basolateral receptor Adenylate cyclase cAMP → urine

↑ plasma osmolarity ↓ blood volume

Fast

Basolateral V2 receptor Adenylate cyclase cAMP (Note: V1 receptors are on blood vessels; mechanism is Ca2+−IP3)

↓ phosphate reabsorption (proximal tubule) ↑ Ca2+ reabsorption (distal tubule) Stimulates 1α-hydroxylase (proximal tubule) ↑ H2O permeability (late distal tubule and collecting duct principal cells)

ADH

Aldosterone

↓ blood volume (via renin– angiotensin II) ↑ plasma [K+]

Slow

New protein synthesis

↑ Na+ reabsorption (ENaC, distal tubule principal cells) ↑ K+ secretion (distal tubule principal cells) ↑ H+ secretion (distal tubule α-intercalated cells)

ANP

↑ atrial pressure

Fast

Guanylate cyclase cGMP

↑ GFR ↓ Na+ reabsorption

Angiotensin II

↓ blood volume (via renin)

Fast

↑ Na+−H+ exchange and HCO3− reabsorption (proximal tubule)

ADH = antidiuretic hormone; ANP = atrial natriuretic peptide; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; GFR = glomerular filtration rate; PTH = parathyroid hormone; EnaC = epithelial Na+ channel.

■

Carbonic anhydrase, which is present in most cells, catalyzes the reversible reaction between CO2 and H2O.

2. Nonvolatile acids ■ ■ ■ ■

are also called fixed acids. include sulfuric acid (a product of protein catabolism) and phosphoric acid (a product of phospholipid catabolism). are normally produced at a rate of 40–60 mmoles/day. Other fixed acids that may be overproduced in disease or may be ingested include ketoacids, lactic acid, and salicylic acid.

B. Buffers ■ ■

prevent a change in pH when H+ ions are added to or removed from a solution. are most effective within 1.0 pH unit of the pK of the buffer (i.e., in the linear portion of the titration curve).

1. Extracellular buffers a. The major extracellular buffer is HCO3-, which is produced from CO2 and H2O. ■

The pK of the CO2/HCO3− buffer pair is 6.1.

b. Phosphate is a minor extracellular buffer. ■

The pK of the H2PO4−/HPO4−2 buffer pair is 6.8.

■

Phosphate is most important as a urinary buffer; excretion of H+ as H2PO4− is called titratable acid.


170


2. Intracellular buffers a. Organic phosphates [e.g., AMP, ADP, ATP, 2,3-diphosphoglycerate (DPG)] b. Proteins ■ ■ ■

Imidazole and α-amino groups on proteins have pKs that are within the physiologic pH range. Hemoglobin is a major intracellular buffer. In the physiologic pH range, deoxyhemoglobin is a better buffer than oxyhemoglobin.

3. Using the Henderson–Hasselbalch equation to calculate pH pH ⴝ pK ⴙ log where: pH pK [A–] [HA] ■ ■ ■ ■

= = = =

[ Aⴚ ] [HA ]

–log10 [H+] (pH units) –log10 equilibrium constant (pH units) base form of buffer (mM) acid form of buffer (mM)

A−, the base form of the buffer, is the H+ acceptor. HA, the acid form of the buffer, is the H+ donor. When the concentrations of A– and HA are equal, the pH of the solution equals the pK of the buffer, as calculated by the Henderson–Hasselbalch equation. Example: The pK of the H2PO4−/HPO4−2 buffer pair is 6.8. What are the relative concentrations of H2PO4− and HPO4−2 in a urine sample that has a pH of 4.8? pH = pK + log 4.8 = 6.8 + log log

HPO4

−2

H2PO4 − HPO4 −2 H2PO4 − H2PO4 − HPO4 −2

HPO4 −2 H2PO4 − HPO4 −2 H2PO4 −

= −2.0 = 0.01 = 100

For this buffer pair, HPO4−2 is A− and H2PO4− is HA. Thus, the Henderson–Hasselbalch equation can be used to calculate that the concentration of H2PO4− is 100 times that of HPO4−2 in a urine sample of pH 4.8.

4. Titration curves (Figure 5-18) ■ ■ ■ ■

describe how the pH of a buffered solution changes as H+ ions are added to it or removed from it. As H+ ions are added to the solution, the HA form is produced; as H+ ions are removed, the A− form is produced. A buffer is most effective in the linear portion of the titration curve, where the addition or removal of H+ causes little change in pH. According to the Henderson–Hasselbalch equation, when the pH of the solution equals the pK, the concentrations of HA and A– are equal.

C. Renal acid–base 1. Reabsorption of filtered HCO3– (Figure 5-19) ■

occurs primarily in the proximal tubule.


171


H+ removed

HA

H+ added

pK

A– 3

4

FIGURE 5-18 Titration curve for a weak acid (HA) and its conjugate base (A−).

5

6

7 pH

8

9

10

a. Key features of reabsorption of filtered HCO3– (1) H+ and HCO3− are produced in the proximal tubule cells from CO2 and H2O. CO2 and H2O combine to form H2CO3, catalyzed by intracellular carbonic anhydrase;

H2CO3 dissociates into H+ and HCO3–. H+ is secreted into the lumen via the Na+-H+ exchange mechanism in the luminal membrane. The HCO3– is reabsorbed. (2) In the lumen, the secreted H+ combines with filtered HCO3– to form H2CO3, which dissociates into CO2 and H2O, catalyzed by brush border carbonic anhydrase. CO2 and H2O diffuse into the cell to start the cycle again. (3) The process results in net reabsorption of filtered HCO3–. However, it does not result in net secretion of H+.

b. Regulation of reabsorption of filtered HCO3– (1) Filtered load ■

Increases in the filtered load of HCO3– result in increased rates of HCO3– reabsorption. However, if the plasma HCO3– concentration becomes very high (e.g., metabolic alkalosis), the filtered load will exceed the reabsorptive capacity, and HCO3– will be excreted in the urine.

(2) PCO2 ■

■

Increases in PCO2 result in increased rates of HCO3– reabsorption because supply of intracellular H+ for secretion is increased. This mechanism is basis for the renal compensation for respiratory acidosis. Decreases in PCO2 result in decreased rates of HCO3– reabsorption because supply of intracellular H+ for secretion is decreased. This mechanism is basis for the renal compensation for respiratory alkalosis.

Lumen

Cell Na+

HCO3– + H+ (filtered) H2CO3 CA CO2 + H2O

H+

Blood Na+

H+ + HCO3– H2CO3

K+ Filtered HCO3– is reabsorbed

CA CO2 + H2O

FIGURE 5-19 Mechanism for reabsorption of filtered HCO3– in the proximal tubule. CA = carbonic anhydrase.

the the the the


172

Board Review Series: Physiology Lumen

Intercalated cell

Blood Na+

HPO4–2 + H+ (filtered)

H+ + HCO3– H2CO3

K+ “New” HCO3– is reabsorbed

CA CO2 + H2O H2PO4– Titratable acid is excreted FIGURE 5-20 Mechanism for excretion of H+ as titratable acid. CA = carbonic anhydrase.

(3) ECF volume ■ ■

ECF volume expansion results in decreased HCO3− reabsorption. ECF volume contraction results in increased HCO3− reabsorption (contraction alkalosis).

(4) Angiotensin II ■

stimulates Na+–H+ exchange and thus increases HCO3− reabsorption, contributing to the contraction alkalosis that occurs secondary to ECF volume contraction.

2. Excretion of fixed H+ Fixed H+ produced from the catabolism of protein and phospholipid is excreted by two mechanisms, titratable acid and NH4+. a. Excretion of H+ as titratable acid (H2PO4–) [Figure 5-20] ■

■

The amount of H+ excreted as titratable acid depends on the amount of urinary buffer present (usually HPO4−2) and the pK of the buffer.

(1) H+ and HCO3– are produced in the cell from CO2 and H2O. The H+ is secreted into the lumen by an H+-ATPase, and the HCO3– is reabsorbed into the blood (“new” HCO3–). In the urine, the secreted H+ combines with filtered HPO4–2 to form H2PO4–, which is excreted as titratable acid. The H+-ATPase is increased by aldosterone. (2) This process results in net secretion of H+ and net reabsorption of newly synthesized HCO3–. (3) As a result of H+ secretion, the pH of urine becomes progressively lower. The minimum urinary pH is 4.4. (4) The amount of H+ excreted as titratable acid is determined by the amount of urinary buffer and the pK of the buffer. b. Excretion of H+ as NH4+ (Figure 5-21) ■

The amount of H+ excreted as NH4+ depends on both the amount of NH3 synthesized by renal cells and the urine pH.

(1) NH3 is produced in renal cells from glutamine. It diffuses down its concentration gradient from the cells into the lumen. (2) H+ and HCO3– are produced in the cells from CO2 and H2O. The H+ is secreted into the lumen via an H+-ATPase and combines with NH3 to form NH4+, which is excreted (diffusion trapping). The HCO3− is reabsorbed into the blood (“new” HCO3−). (3) The lower the pH of the tubular fluid, the greater the excretion of H+ as NH4+; at low urine pH, there is more NH4+ relative to NH3 in the urine, thus increasing the gradient for NH3 diffusion. (4) In acidosis, an adaptive increase in NH3 synthesis occurs and aids in the excretion of excess H+.


Chapter 5 Renal and Acid–Base Physiology Cell

Lumen

173

Blood Na+

H+

H+ +

+

–

HCO3

K+

NH3

NH3

“New” HCO3– is reabsorbed

H2CO3 Glutamine

NH4+ excreted

CA CO2 + H2O

FIGURE 5-21 Mechanism for excretion of H+ as NH4+. CA = carbonic anhydrase.

(5) Hyperkalemia inhibits NH3 synthesis, which produces a decrease in H+ excretion as NH+4 [type 4 renal tubular acidosis (RTA)]. Conversely, hypokalemia stimulates NH3 synthesis, which produces an increase in H+ excretion.

D. Acid–base disorders (Tables 5-8 and 5-9 and Figure 5-22) ■

The expected compensatory responses to simple acid–base disorders can be calculated as shown in Table 5-10. If the actual response equals the calculated (predicted) response, then one acid–base disorder is present. If the actual response differs from the calculated response, then more than one acid–base disorder is present.

1. Metabolic acidosis a. Overproduction or ingestion of fixed acid or loss of base produces an increase in arterial [H+] (acidemia). b. HCO3− is used to buffer the extra fixed acid. As a result, the arterial [HCO3–] decreases. This decrease is the primary disturbance. c. Acidemia causes hyperventilation (Kussmaul breathing), which is the respiratory compensation for metabolic acidosis. d. Correction of metabolic acidosis consists of increased excretion of the excess fixed H+ as titratable acid and NH4+, and increased reabsorption of “new” HCO3−, which replenishes the HCO3− used in buffering the added fixed H+. In chronic metabolic acidosis, an adaptive increase in NH3 synthesis aids in the excretion of excess H+. e. Serum anion gap = [Na+]–([Cl−] + [HCO3−]) (Figure 5-23) ■

■ ■

The serum anion gap represents unmeasured anions in serum. These unmeasured anions include phosphate, citrate, sulfate, and protein. The normal value of the serum anion gap is 12 mEq/L (range, 8–16 mEq/L)

t a b l e

5-8

Summary of Acid–Base Disorders ↔

Disorder

CO2 + H2O

Metabolic acidosis

Respiratory acidosis

↓ (respiratory compensation) ↑ (respiratory compensation) ä

Respiratory alkalosis

å

Metabolic alkalosis

Heavy arrows indicate primary disturbance.

HCO3-

Respiratory Compensation

↑

å

Hyperventilation

↓

ä

Hypoventilation

↑

↑

None

↓

↓

None

H+

+

Renal Compensation

↑ H+ excretion ↑ HCO3− reabsorption ↓ H+ excretion ↓ HCO3− reabsorption


174


5-9

t a b l e

Metabolic acidosis

Causes of Acid–Base Disorders Example

Comments

Ketoacidosis

Accumulation of β-OH-butyric acid and acetoacetic acid ↑ anion gap Accumulation of lactic acid during hypoxia ↑ anion gap Failure to excrete H+ as titratable acid and NH4+ ↑ anion gap Also causes respiratory alkalosis ↑ anion gap Produces formic acid ↑ anion gap Produces glycolic and oxalic acids ↑ anion gap GI loss of HCO3− Normal anion gap Renal loss of HCO3− Normal anion gap Failure to excrete titratable acid and NH4+; failure to acidify urine Normal anion gap Hypoaldosteronism; failure to excrete NH4+ Hyperkalemia caused by lack of aldosterone inhibits NH3 synthesis Normal anion gap Loss of gastric H+; leaves HCO3− behind in blood Worsened by volume contraction Hypokalemia May have ↑ anion gap because of production of ketoacids (starvation) Increased H+ secretion by distal tubule; increased new HCO3− reabsorption Volume contraction alkalosis

Lactic acidosis Chronic renal failure Salicylate intoxication Methanol/formaldehyde intoxication Ethylene glycol intoxication Diarrhea Type 2 RTA Type 1 RTA Type 4 RTA

Metabolic alkalosis

Vomiting

Hyperaldosteronism Loop or thiazide diuretics Respiratory acidosis

Opiates; sedatives; anesthetics Guillain–Barré syndrome; polio; ALS; multiple sclerosis Airway obstruction Adult respiratory distress syndrome; COPD

Inhibition of medullary respiratory center Weakening of respiratory muscles ↓ CO2 exchange in lungs

Respiratory alkalosis

Pneumonia; pulmonary embolus High altitude Psychogenic Salicylate intoxication

Hypoxemia causes ↑ ventilation rate Hypoxemia causes ↑ ventilation rate Direct stimulation of medullary respiratory center; also causes metabolic acidosis

ALS = amyotrophic lateral sclerosis; COPD = chronic obstructive pulmonary disease; GI = gastrointestinal; RTA = renal tubular acidosis.

In metabolic acidosis, the serum [HCO3−] decreases as it is depleted in buffering fixed acid. For electroneutrality, the concentration of another anion must increase to replace HCO3−. That anion can be Cl– or it can be an unmeasured anion. (1) The serum anion gap is increased if the concentration of an unmeasured anion (e.g., phosphate, lactate, β-hydroxybutyrate, and formate) is increased to replace HCO3−. (2) The serum anion gap is normal if the concentration of Cl– is increased to replace HCO3− (hyperchloremic metabolic acidosis). ■

2. Metabolic alkalosis a. Loss of fixed H+ or gain of base produces a decrease in arterial [H+] (alkalemia). b. As a result, arterial [HCO3−] increases. This increase is the primary disturbance. ■

For example, in vomiting, H+ is lost from the stomach, HCO3− remains behind in the blood, and the [HCO3−] increases.


175


100

80

PCO2 (mm Hg)

60

40

20

0 0

12

24 [HCO3–

36

48

60

] (mEq/L)

FIGURE 5-22 Acid–base map with values for simple acid–base disorders superimposed. The relationships are shown between arterial PCO2, [HCO3–], and pH. The ellipse in the center shows the normal range of values. Shaded areas show the range of values associated with simple acid–base disorders. Two shaded areas are shown for each respiratory disorder: one for the acute phase and one for the chronic phase. (Adapted with permission from Cohen JJ, Kassirer JP. Acid/Base. Boston: Little, Brown; 1982.)

c. Alkalemia causes hypoventilation, which is the respiratory compensation for metabolic alkalosis. d. Correction of metabolic alkalosis consists of increased excretion of HCO3− because the filtered load of HCO3− exceeds the ability of the renal tubule to reabsorb it. ■

If metabolic alkalosis is accompanied by ECF volume contraction (e.g., vomiting), the reabsorption of HCO3− increases (secondary to ECF volume contraction and activation of the renin–angiotensin II–aldosterone system), worsening the metabolic alkalosis (i.e., contraction alkalosis).

3. Respiratory acidosis ■

is caused by a decrease in respiratory rate and retention of CO2.

a. Increased arterial PCO2, which is the primary disturbance, causes an increase in [H+] and [HCO3–] by mass action. b. There is no respiratory compensation for respiratory acidosis.


176


t a b l e

5-10

Calculating Compensatory Responses to Simple Acid–Base Disorders

Acid–Base Disturbance

Primary Disturbance

Compensation

Metabolic acidosis

↓ [HCO3−]

↓ PCO2

Metabolic alkalosis

↑ [HCO3−]

↑ PCO2

Respiratory acidosis Acute

↑ PCO2

↑ [HCO3−]

↑ PCO2

↑ [HCO3−]

↓ PCO2

↓ [HCO3−]

↓ PCO2

↓ [HCO3−]

Chronic Respiratory alkalosis Acute Chronic

Predicted Compensatory Response 1 mEq/L decrease in HCO3− → 1.3 mm Hg decrease in PCO2 1 mEq/L increase in HCO3− → 0.7 mm Hg increase in PCO2 1 mm Hg increase in PCO2 → 0.1 mEq/L increase in HCO3− 1 mm Hg increase in PCO2 → 0.4 mEq/L increase in HCO3− 1 mm Hg decrease in PCO2 → 0.2 mEq/L decrease in HCO3− 1 mm Hg decrease in PCO2 → 0.4 mEq/L decrease in HCO3−

c. Renal compensation consists of increased excretion of H+ as titratable acid and NH4+,

and increased reabsorption of “new” HCO3–. This process is aided by the increased PCO2, which supplies more H+ to the renal cells for secretion. The resulting increase in serum [HCO3–] helps to normalize the pH.

■ ■

In acute respiratory acidosis, renal compensation has not yet occurred. In chronic respiratory acidosis, renal compensation (increased HCO3– reabsorption) has occurred. Thus, arterial pH is increased toward normal (i.e., a compensation).

4. Respiratory alkalosis ■

is caused by an increase in respiratory rate and loss of CO2.

a. Decreased arterial PCO2, which is the primary disturbance, causes a decrease in [H+] and [HCO3–] by mass action. b. There is no respiratory compensation for respiratory alkalosis. c. Renal compensation consists of decreased excretion of H+ as titratable acid and NH4+, and decreased reabsorption of “new” HCO3–. This process is aided by the decreased

Anion gap HCO3–

Unmeasured anions = protein, phosphate, citrate, sulfate

Na+ Cl–

Cations

Anions

FIGURE 5-23 Serum anion gap.



177

PCO2, which causes a deficit of H+ in the renal cells for secretion. The resulting decrease in serum [HCO3–] helps to normalize the pH. ■ ■

In acute respiratory alkalosis, renal compensation has not yet occurred. In chronic respiratory alkalosis, renal compensation (decreased HCO3– reabsorption) has occurred. Thus, arterial pH is decreased toward normal (i.e., a compensation).

d. Symptoms of hypocalcemia (e.g., tingling, numbness, muscle spasms) may occur because H+ and Ca2+ compete for binding sites on plasma proteins. Decreased [H+] causes increased protein binding of Ca2+ and decreased free ionized Ca2+.

X. DIURETICS (TABLE 5-11) XI. INTEGRATIVE EXAMPLES A. Hypoaldosteronism 1. Case study ■

A woman has a history of weakness, weight loss, orthostatic hypotension, increased pulse rate, and increased skin pigmentation. She has decreased serum [Na+], decreased serum osmolarity, increased serum [K+], and arterial blood gases consistent with metabolic acidosis.

2. Explanation of hypoaldosteronism a. The lack of aldosterone has three direct effects on the kidney: decreased Na+ reabsorption, decreased K+ secretion, and decreased H+ secretion. As a result, there is ECF

t a b l e

5-11

Effects of Diuretics on the Nephron

Class of Diuretic

Site of Action

Mechanism

Major Effects

Carbonic anhydrase inhibitors (acetazolamide) Loop diuretics (furosemide, ethacrynic acid, bumetanide)

Proximal tubule

Inhibition of carbonic anhydrase Inhibition of Na+–K+ –2Cl– cotransport

↑ HCO3– excretion

Thick ascending limb of the loop of Henle

Thiazide diuretics (chlorothiazide, hydrochlorothiazide)

Early distal tubule (cortical diluting segment)

Inhibition of Na+–Cl– cotransport

K+-sparing diuretics (spironolactone, triamterene, amiloride)

Late distal tubule and collecting duct

Inhibition of Na+ reabsorption Inhibition of K+ secretion Inhibition of H+ secretion

↑ NaCl excretion ↑ K+ excretion (↑ distal tubule flow rate) ↑ Ca2+ excretion (treat hypercalcemia) ↓ ability to concentrate urine (↓ corticopapillary gradient) ↓ ability to dilute urine (inhibition of diluting segment) ↑ NaCl excretion ↑ K+ excretion (↑ distal tubule flow rate) ↓ Ca2+ excretion (treatment of idiopathic hypercalciuria) ↓ ability to dilute urine (inhibition of cortical diluting segment) No effect on ability to concentrate urine ↑ Na+ excretion (small effect) ↓ K+ excretion (used in combination with loop or thiazide diuretics) ↓ H+ excretion


178


volume contraction (caused by decreased Na+ reabsorption), hyperkalemia (caused by decreased K+ secretion), and metabolic acidosis (caused by decreased H+ secretion). b. The ECF volume contraction is responsible for this woman’s orthostatic hypotension. The decreased arterial pressure produces an increased pulse rate via the baroreceptor mechanism.

c. ECF volume contraction also stimulates ADH secretion from the posterior pituitary via volume receptors. ADH causes increased water reabsorption from the collecting ducts, which results in decreased serum [Na+] (hyponatremia) and decreased serum osmolarity. Thus, ADH released by a volume mechanism is “inappropriate” for the serum osmolarity in this case. d. Hyperpigmentation is caused by adrenal insufficiency. Decreased levels of cortisol produce increased secretion of adrenocorticotropic hormone (ACTH) by negative feedback. ACTH has pigmenting effects similar to those of melanocyte-stimulating hormone.

B. Vomiting 1. Case study A man is admitted to the hospital for evaluation of severe epigastric pain. He has had persistent nausea and vomiting for 4 days. Upper gastrointestinal (GI) endoscopy shows a pyloric ulcer with partial gastric outlet obstruction. He has orthostatic hypotension, decreased serum [K+], decreased serum [Cl–], arterial blood gases consistent with metabolic alkalosis, and decreased ventilation rate. 2. Responses to vomiting (Figure 5-24) a. Loss of H+ from the stomach by vomiting causes increased blood [HCO3−] and metabolic alkalosis. Because Cl– is lost from the stomach along with H+, hypochloremia and ECF volume contraction occur. b. The decreased ventilation rate is the respiratory compensation for metabolic alkalosis. c. ECF volume contraction is associated with decreased blood volume and decreased renal perfusion pressure. As a result, renin secretion is increased, production of angiotensin II is increased, and secretion of aldosterone is increased. Thus, the ECF volume contraction worsens the metabolic alkalosis because angiotensin II increases HCO3– reabsorption in the proximal tubule (contraction alkalosis). d. The increased levels of aldosterone (secondary to ECF volume contraction) cause increased distal K+ secretion and hypokalemia. Increased aldosterone also causes increased distal H+ secretion, further worsening the metabolic alkalosis. e. Treatment consists of NaCl infusion to correct ECF volume contraction (which is maintaining the metabolic alkalosis and causing hypokalemia) and administration of K+ to replace K+ lost in the urine. ■

C. Diarrhea 1. Case study ■

A man returns from a trip abroad with “traveler’s diarrhea.” He has weakness, weight loss, orthostatic hypotension, increased pulse rate, increased breathing rate, pale skin, a serum [Na+] of 132 mEq/L, a serum [Cl–] of 111 mEq/L, and a serum [K+] of 2.3 mEq/L. His arterial blood gases are: pH, 7.25; PCO2, 24 mm Hg; HCO3–, 10.2 mEq/L.

2. Explanation of responses to diarrhea a. Loss of HCO3– from the GI tract causes a decrease in the blood [HCO3−] and, accord-

ing to the Henderson–Hasselbalch equation, a decrease in blood pH. Thus, this man has metabolic acidosis. b. To maintain electroneutrality, the HCO3– lost from the body is replaced by Cl−, a measured anion; thus, there is a normal anion gap. The serum anion gap = [Na+] – ([Cl−] + [HCO3–]) = 132 – (111 + 10.2) = 10.8 mEq/L. c. The increased breathing rate (hyperventilation) is the respiratory compensation for meta-

bolic acidosis.



179

Vomiting

Loss of gastric HCl

ECF volume contraction

Renal perfusion pressure

Loss of fixed H+

Angiotensin II

Aldosterone

Na+–H+ exchange

HCO3 – reabsorption

Metabolic alkalosis (generation)

H+ secretion

Metabolic alkalosis (maintenance)

K+ secretion

Hypokalemia

FIGURE 5-24 Metabolic alkalosis caused by vomiting. ECF = extracellular fluid.

d. As a result of his diarrhea, this man has ECF volume contraction, which leads to decreases in blood volume and arterial pressure. The decrease in arterial pressure activates the baroreceptor reflex, resulting in increased sympathetic outflow to the heart and blood vessels. The increased pulse rate is a consequence of increased sympathetic activity in the sinoatrial (SA) node, and the pale skin is the result of cutaneous vasoconstriction. e. ECF volume contraction also activates the renin–angiotensin–aldosterone system. Increased levels of aldosterone lead to increased distal K+ secretion and hypokalemia. Loss of K+ in diarrhea fluid also contributes to hypokalemia. f. Treatment consists of replacing all fluid and electrolytes lost in diarrhea fluid and urine, including Na+, HCO3−, and K+.


Review Test 1. Secretion of K+ by the distal tubule will be

5. Use the values below to answer the fol-

decreased by

lowing question.

(A) (B) (C) (D) (E)

Glomerular capillary hydrostatic pressure = 47 mm Hg Bowman’s space hydrostatic pressure = 10 mm Hg Bowman’s space oncotic pressure = 0 mm Hg At what value of glomerular capillary oncotic pressure would glomerular filtration stop?

metabolic alkalosis a high-K+ diet hyperaldosteronism spironolactone administration thiazide diuretic administration

2. Subjects A and B are 70-kg men. Subject A drinks 2 L of distilled water, and subject B drinks 2 L of isotonic NaCl. As a result of these ingestions, subject B will have a

(A) greater change in intracellular fluid (ICF) volume

(B) higher positive free-water clearance (CH O) 2

(C) greater change in plasma osmolarity (D) higher urine osmolarity (E) higher urine flow rate Questions 3 and 4

(A) (B) (C) (D) (E)

57 mm Hg 47 mm Hg 37 mm Hg 10 mm Hg 0 mm Hg

6. The reabsorption of filtered HCO3– (A) results in reabsorption of less than 50%

A 45-year-old woman develops severe diarrhea while on vacation. She has the following arterial blood values:

(B) (C)

pH = 7.25 PcO2 = 24 mm Hg

(D)

of the filtered load when the plasma concentration of HCO3– is 24 mEq/L acidifies tubular fluid to a pH of 4.4 is directly linked to excretion of H+ as NH4+ is inhibited by decreases in arterial PcO2 can proceed normally in the presence of a renal carbonic anhydrase inhibitor

[HCO3–] = 10 mEq/L Venous blood samples show decreased blood [K+] and a normal anion gap.

(E)

3. The correct diagnosis for this patient is (A) metabolic acidosis (B) metabolic alkalosis (C) respiratory acidosis (D) respiratory alkalosis (E) normal acid–base status

in a 20-year-old college student who was participating in a research study in the Clinical Research Unit:

7. The following information was obtained

Plasma

Urine

[Inulin] = 1 mg/mL [X] = 2 mg/mL

[Inulin] = 150 mg/mL [X] = 100 mg/mL Urine flow rate = 1 mL/min

4. Which of the following statements about this patient is correct? (A) She is hypoventilating (B) The decreased arterial [HCO3–] is a result

of buffering of excess H+ by HCO3– (C) The decreased blood [K+] is a result of exchange of intracellular H+ for extracellular K+ (D) The decreased blood [K+] is a result of increased circulating levels of aldosterone (E) The decreased blood [K+] is a result of decreased circulating levels of antidiuretic hormone (ADH)

180

Assuming that X is freely filtered, which of the following statements is most correct?

(A) There is net secretion of X (B) There is net reabsorption of X (C) There is both reabsorption and secretion of X

(D) The clearance of X could be used to measure the glomerular filtration rate (GFR) (E) The clearance of X is greater than the clearance of inulin



8. To maintain normal H+ balance, total daily excretion of H+ should equal the daily

(A) fixed acid production plus fixed acid (B) (C) (D) (E)

ingestion HCO3– excretion HCO3– filtered load titratable acid excretion filtered load of H+

181

(D) 10 times that of A– (E) 100 times that of A– 13. Which of the following would produce an increase in the reabsorption of isosmotic fluid in the proximal tubule?

(A) Increased filtration fraction (B) Extracellular fluid (ECF) volume expansion

9. One gram of mannitol was injected into a woman. After equilibration, a plasma sample had a mannitol concentration of 0.08 g/L. During the equilibration period, 20% of the injected mannitol was excreted in the urine. The subject’s

(A) (B) (C) (D) (E)

extracellular fluid (ECF) volume is 1 L intracellular fluid (ICF) volume is 1 L ECF volume is 10 L ICF volume is 10 L interstitial volume is 12.5 L

10. At plasma concentrations of glucose higher than occur at transport maximum (Tm), the (A) clearance of glucose is zero (B) excretion rate of glucose equals the filtration rate of glucose

(C) reabsorption rate of glucose equals the filtration rate of glucose

(D) excretion rate of glucose increases with increasing plasma glucose concentrations (E) renal vein glucose concentration equals the renal artery glucose concentration

11. A negative free-water clearance (–CH O) 2 will occur in a person who (A) drinks 2 L of distilled water in 30 minutes

(B) begins excreting large volumes of urine with an osmolarity of 100 mOsm/L after a severe head injury (C) is receiving lithium treatment for depression, and has polyuria that is unresponsive to the administration of antidiuretic hormone (ADH) (D) has an oat cell carcinoma of the lung, and excretes urine with an osmolarity of 1000 mOsm/L

12. A buffer pair (HA/A–) has a pK of 5.4. At a blood pH of 7.4, the concentration of HA is (A) 1/100 that of A– (B) 1/10 that of A– (C) equal to that of A–

(C) Decreased peritubular capillary protein concentration

(D) Increased peritubular capillary hydrostatic pressure

(E) Oxygen deprivation 14. Which of the following substances or combinations of substances could be used to measure interstitial fluid volume? (A) (B) (C) (D) (E)

Mannitol D2O alone Evans blue Inulin and D2O Inulin and radioactive albumin

15. At plasma para-aminohippuric acid (PAH) concentrations below the transport maximum (Tm), PAH

(A) (B) (C) (D)

reabsorption is not saturated clearance equals inulin clearance secretion rate equals PAH excretion rate concentration in the renal vein is close to zero (E) concentration in the renal vein equals PAH concentration in the renal artery

16. Compared with a person who ingests 2 L of distilled water, a person with water deprivation will have a

(A) higher free-water clearance (CH O) 2 (B) lower plasma osmolarity (C) lower circulating level of antidiuretic hormone (ADH)

(D) higher tubular fluid/plasma (TF/P) osmolarity in the proximal tubule

(E) higher rate of H2O reabsorption in the collecting ducts

17. Which of the following would cause an increase in both glomerular filtration rate (GFR) and renal plasma flow (RPF)?

(A) (B) (C) (D) (E)

Hyperproteinemia A ureteral stone Dilation of the afferent arteriole Dilation of the efferent arteriole Constriction of the efferent arteriole


182


18. A patient has the following arterial blood

22. A woman has a plasma osmolarity of

values:

300 mOsm/L and a urine osmolarity of 1200 mOsm/L. The correct diagnosis is

pH = 7.52 PCO2 = 20 mm Hg [HCO3–] = 16 mEq/L Which of the following statements about this patient is most likely to be correct?

(A) He is hypoventilating (B) He has decreased ionized [Ca2+] in blood (C) He has almost complete respiratory compensation (D) He has an acid–base disorder caused by overproduction of fixed acid (E) Appropriate renal compensation would cause his arterial [HCO3–] to increase

19. Which of the following would best distinguish an otherwise healthy person with severe water deprivation from a person with the syndrome of inappropriate antidiuretic hormone (SIADH)?

(A) (B) (C) (D)

Free-water clearance (CH O) 2 Urine osmolarity Plasma osmolarity Circulating levels of antidiuretic hormone (ADH) (E) Corticopapillary osmotic gradient

20. Which of the following causes a decrease in renal

Ca2+

clearance?

(A) (B) (C) (D)

Hypoparathyroidism Treatment with chlorothiazide Treatment with furosemide Extracellular fluid (ECF) volume expansion (E) Hypermagnesemia

21. A patient arrives at the emergency room with low arterial pressure, reduced tissue turgor, and the following arterial blood values: pH = 7.69 [HCO3–] = 57 mEq/L PCO2 = 48 mm Hg

(A) syndrome of inappropriate antidiuretic (B) (C) (D) (E)

hormone (SIADH) water deprivation central diabetes insipidus nephrogenic diabetes insipidus drinking large volumes of distilled water

23. A patient is infused with paraaminohippuric acid (PAH) to measure renal blood flow (RBF). She has a urine flow rate of 1 mL/min, a plasma [PAH] of 1 mg/mL, a urine [PAH] of 600 mg/mL, and a hematocrit of 45%. What is her “effective” RBF?

(A) (B) (C) (D)

600 mL/min 660 mL/min 1091 mL/min 1333 mL/min

24. Which of the following substances has the highest renal clearance?

(A) (B) (C) (D) (E)

Para-aminohippuric acid (PAH) Inulin Glucose Na+ Cl–

25. A woman runs a marathon in 90°F weather and replaces all volume lost in sweat by drinking distilled water. After the marathon, she will have

(A) decreased total body water (TBW) (B) decreased hematocrit (C) decreased intracellular fluid (ICF) volume

(D) decreased plasma osmolarity (E) increased intracellular osmolarity 26. Which of the following causes hyperkalemia?

Which of the following responses would also be expected to occur in this patient?

(A) (B) (C) (D) (E)

(A) Hyperventilation (B) Decreased K+ secretion by the distal

27. Which of the following is a cause of

tubules (C) Increased ratio of H2PO4– to HPO4–2 in urine (D) Exchange of intracellular H+ for extracellular K+

(A) (B) (C) (D)

Exercise Alkalosis Insulin injection Decreased serum osmolarity Treatment with β-agonists

metabolic alkalosis? Diarrhea Chronic renal failure Ethylene glycol ingestion Treatment with acetazolamide


183


(eating a normal protein diet) and decreased urinary excretion of NH4+?

(E) Hyperaldosteronism (F)

Salicylate poisoning

pH 28. Which of the following is an action of parathyroid hormone (PTH) on the renal tubule?

(A) Stimulation of adenylate cyclase (B) Inhibition of distal tubule K+ secretion (C) Inhibition of distal tubule Ca2+ reabsorption

(D) Stimulation of proximal tubular phosphate reabsorption

(E) Inhibition of production of 1,25-dihydroxycholecalciferol

and hypokalemia. Measurement of his arterial blood gases reveals a pH of 7.5 and a calculated HCO3– of 32 mEq/L. His serum cortisol and urinary vanillylmandelic acid (VMA) are normal, his serum aldosterone is increased, and his plasma renin activity is decreased. Which of the following is the most likely cause of his hypertension? Cushing’s syndrome Cushing’s disease Conn’s syndrome Renal artery stenosis Pheochromocytoma

describes a heavy smoker with a history of emphysema and chronic bronchitis who is becoming increasingly somnolent?

(A) (B) (C) (D) (E)

7.65 7.50 7.40 7.32 7.31

HCO3– (mEq/L) 48 15 24 30 16

PCO2 (mm Hg)

45 20 40 60 33

HCO3– (mEq/L) 48 15 24 30 16

PCO2 (mm Hg)

45 20 40 60 33

33. Which set of arterial blood values describes a patient with untreated diabetes mellitus and increased urinary excretion of NH4+?

(A) (B) (C) (D) (E)

7.65 7.50 7.40 7.32 7.31

HCO3– (mEq/L)

48 15 24 30 16

PCO2 (mm Hg) 45 20 40 60 33

34. Which set of arterial blood values describes a patient with a 5-day history of vomiting? pH (A) (B) (C) (D) (E)

30. Which set of arterial blood values

pH

7.65 7.50 7.40 7.32 7.31

pH

Questions 29–33 29. A man presents with hypertension

(A) (B) (C) (D) (E)

(A) (B) (C) (D) (E)

7.65 7.50 7.40 7.32 7.31

HCO3– (mEq/L)

48 15 24 30 16

PCO2 (mm Hg)

45 20 40 60 33

The following figure applies to Questions 35–39.

A B D

31. Which set of arterial blood values describes a patient with partially compensated respiratory alkalosis after 1 month on a mechanical ventilator?

pH (A) (B) (C) (D) (E)

7.65 7.50 7.40 7.32 7.31

HCO3–(mEq/L) 48 15 24 30 16

PCO2 (mm Hg)

45 20 40 60 33

32. Which set of arterial blood values describes a patient with chronic renal failure

E C


184


35. At which nephron site does the

(A) (B) (C) (D) (E)

Site A Site B Site C Site D Site E

D Percent filtered load remaining

amount of K+ in tubular fluid exceed the amount of filtered K+ in a person on a high-K+ diet?

A Bowman's space

36. At which nephron site is the tubular fluid/plasma (TF/P) osmolarity lowest in a person who has been deprived of water?

(A) (B) (C) (D) (E)


37. At which nephron site is the tubular fluid inulin concentration highest during antidiures is?

(A) (B) (C) (D) (E)


38. At which nephron site is the tubular fluid inulin concentration lowest?

(A) (B) (C) (D) (E)


39. At which nephron site is the tubular fluid glucose concentration highest?

(A) (B) (C) (D) (E)


The following graph applies to Questions 41–43. The curves show the percentage of the filtered load remaining in the tubular fluid at various sites along the specimen.

C

100%

B Proximal tubule

Distal tubule

Urine

40. Which curve describes the inulin profile along the nephron?

(A) (B) (C) (D)

Curve A Curve B Curve C Curve D

41. Which curve describes the alanine profile along the nephron?

(A) (B) (C) (D)


42. Which curve describes the paraaminohippuric acid (PAH) profile along the nephron?

(A) (B) (C) (D)


43. A person who takes an aspirin (salicylic acid) overdose is treated in the emergency room. The treatment produces a change in urine pH that increases the excretion of salicylic acid. What was the change in urine pH, and what is the mechanism of increased salicylic acid excretion?

(A) Acidification, which converts salicylic acid to its HA form

(B) Alkalinization, which converts salicylic acid to its A– form

(C) Acidification, which converts salicylic acid to its A– form (D) Alkalinization, which converts salicylic acid to its HA form


Answers and Explanations 1. The answer is D [V B 4 b]. Distal K+ secretion is decreased by factors that decrease the

driving force for passive diffusion of K+ across the luminal membrane. Because spironolactone is an aldosterone antagonist, it reduces K+ secretion. Alkalosis, a diet high in K+, and hyperaldosteronism all increase [K+] in the distal cells and thereby increase K+ secretion. Thiazide diuretics increase flow through the distal tubule and dilute the luminal [K+] so that the driving force for K+ secretion is increased.

2. The answer is D [I C 2 a; VII C; Figure 5-15; Table 5-6]. After drinking distilled water, subject A will have an increase in intracellular fluid (ICF) and extracellular fluid (ECF) volumes, a decrease in plasma osmolarity, a suppression of antidiuretic hormone (ADH) secretion, and a positive free-water clearance (CH O), and will produce dilute urine with a 2 high flow rate. Subject B, after drinking the same volume of isotonic NaCl, will have an increase in ECF volume only and no change in plasma osmolarity. Because subject B’s ADH will not be suppressed, he will have a higher urine osmolarity, a lower urine flow rate, and a lower CH O than subject A. 2

3. The answer is A [IX D 1 a–c; Tables 5-8 and 5-9]. An acid pH, together with decreased HCO3– and decreased PCO2, is consistent with metabolic acidosis with respiratory compensation (hyperventilation). Diarrhea causes gastrointestinal (GI) loss of HCO3–, creating a metabolic acidosis.

4. The answer is D [IX D 1 a–c; Tables 5-8 and 5-9]. The decreased arterial [HCO3–] is caused

by gastrointestinal (GI) loss of HCO3– from diarrhea, not by buffering of excess H+ by HCO3–. The woman is hyperventilating as respiratory compensation for metabolic acidosis. Her hypokalemia cannot be the result of the exchange of intracellular H+ for extracellular K+, because she has an increase in extracellular H+, which would drive the exchange in the other direction. Her circulating levels of aldosterone would be increased as a result of extracellular fluid (ECF) volume contraction, which leads to increased K+ secretion by the distal tubule and hypokalemia.

5. The answer is C [II C 4, 5]. Glomerular filtration will stop when the net ultrafiltration pressure across the glomerular capillary is zero; that is, when the force that favors filtration (47 mm Hg) exactly equals the forces that oppose filtration (10 mm Hg + 37 mm Hg).

6. The answer is D [IX C 1 a–b]. Decreases in arterial PCO2 cause a decrease in the reabsorp-

tion of filtered HCO3– by diminishing the supply of H+ in the cell for secretion into the lumen. Reabsorption of filtered HCO3– is nearly 100% of the filtered load and requires carbonic anhydrase in the brush border to convert filtered HCO3– to CO2 to proceed normally. This process causes little acidification of the urine and is not linked to net excretion of H+ as titratable acid or NH4+.

7. The answer is B [II C 1]. To answer this question, calculate the glomerular filtration rate (GFR) and Cx. GFR = 150 mg/mL × 1 mL/min ÷ 1 mg/mL = 150 mL/min. Cx = 100 mg/mL × 1 mL/min ÷ 2 mg/mL = 50 mL/min. Because the clearance of X is less than the clearance of inulin (or GFR), net reabsorption of X must have occurred. Clearance data alone cannot determine whether there has also been secretion of X. Because GFR cannot be measured with a substance that is reabsorbed, X would not be suitable.

8. The answer is A [IX C 2]. Total daily production of fixed H+ from catabolism of proteins

and phospholipids (plus any additional fixed H+ that is ingested) must be matched by the sum of excretion of H+ as titratable acid plus NH4+ to maintain acid–base balance.

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9. The answer is C [I B 1 a]. Mannitol is a marker substance for the extracellular fluid (ECF) volume. ECF volume = amount of mannitol/concentration of mannitol = 1 g – 0.2 g/0.08 g/L = 10 L.

10. The answer is D [III B; Figure 5-5]. At concentrations greater than at the transport maximum (Tm) for glucose, the carriers are saturated so that the reabsorption rate no longer matches the filtration rate. The difference is excreted in the urine. As the plasma glucose concentration increases, the excretion of glucose increases. When it is greater than the Tm, the renal vein glucose concentration will be less than the renal artery concentration because some glucose is being excreted in urine and therefore is not returned to the blood. The clearance of glucose is zero at concentrations lower than at Tm (or lower than threshold) when all of the filtered glucose is reabsorbed, but is greater than zero at concentrations greater than Tm.

11. The answer is D [VII D; Table 5-6]. A person who produces hyperosmotic urine (1000 mOsm/L) will have a negative free-water clearance (–CH2O) [CH2O = V – Cosm]. All of the others will have a positive CH2O because they are producing hyposmotic urine as a result of the suppression of antidiuretic hormone (ADH) by water drinking, central diabetes insipidus, or nephrogenic diabetes insipidus.

12. The answer is A [IX B 3]. The Henderson–Hasselbalch equation can be used to calculate the ratio of HA/A–: pH = 7.4 = 2.0 = 100 =

pK + log A − HA 5.4 + log A − HA log A − HA A − HA or HA A − is 1 100

13. The answer is A [II C 3; IV C 1 d (2)]. Increasing filtration fraction means that a larger portion of the renal plasma flow (RPF) is filtered across the glomerular capillaries. This increased flow causes an increase in the protein concentration and oncotic pressure of the blood leaving the glomerular capillaries. This blood becomes the peritubular capillary blood supply. The increased oncotic pressure in the peritubular capillary blood is a driving force favoring reabsorption in the proximal tubule. Extracellular fluid (ECF) volume expansion, decreased peritubular capillary protein concentration, and increased peritubular capillary hydrostatic pressure all inhibit proximal reabsorption. Oxygen deprivation would also inhibit reabsorption by stopping the Na+–K+ pump in the basolateral membranes.

14. The answer is E [I B 2 b–d]. Interstitial fluid volume is measured indirectly by determining the difference between extracellular fluid (ECF) volume and plasma volume. Inulin, a large fructose polymer that is restricted to the extracellular space, is a marker for ECF volume. Radioactive albumin is a marker for plasma volume.

15. The answer is D [III C; Figure 5-6]. At plasma concentrations that are lower than at the transport maximum (Tm) for para-aminohippuric acid (PAH) secretion, PAH concentration in the renal vein is nearly zero because the sum of filtration plus secretion removes virtually all PAH from the renal plasma. Thus, the PAH concentration in the renal vein is less than that in the renal artery because most of the PAH entering the kidney is excreted in urine. PAH clearance is greater than inulin clearance because PAH is filtered and secreted; inulin is only filtered.

16. The answer is E [VII D; Figures 5-14 and 5-15]. The person with water deprivation will have a higher plasma osmolarity and higher circulating levels of antidiuretic hormone (ADH). These effects will increase the rate of H2O reabsorption in the collecting ducts and create a negative free-water clearance (–CH2O). Tubular fluid/plasma (TF/P) osmolarity in the proximal tubule is not affected by ADH.

17. The answer is C [II C 4; Table 5-3]. Dilation of the afferent arteriole will increase both renal plasma flow (RPF) [because renal vascular resistance is decreased] and glomerular



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filtration rate (GFR) [because glomerular capillary hydrostatic pressure is increased]. Dilation of the efferent arteriole will increase RPF, but decrease GFR. Constriction of the efferent arteriole will decrease RPF (due to increased renal vascular resistance) and increase GFR. Both hyperproteinemia (↑ π in the glomerular capillaries) and a ureteral stone (↑ hydrostatic pressure in Bowman’s space) will oppose filtration and decrease GFR.

18. The answer is B [IX D 4; Table 5-8]. First, the acid–base disorder must be diagnosed. Alkaline pH, low PCO2, and low HCO3– are consistent with respiratory alkalosis. In respiratory alkalosis, the [H+] is decreased and less H+ is bound to negatively charged sites on plasma proteins. As a result, more Ca2+ is bound to proteins and, therefore, the ionized [Ca2+] decreases. There is no respiratory compensation for primary respiratory disorders. The patient is hyperventilating, which is the cause of the respiratory alkalosis. Appropriate renal compensation would be decreased reabsorption of HCO3–, which would cause his arterial [HCO3–] to decrease and his blood pH to decrease (become more normal).

19. The answer is C [VII B, D 4; Table 5-6]. Both individuals will have hyperosmotic urine, a negative free-water clearance (–CH2O), a normal corticopapillary gradient, and high circulating levels of antidiuretic hormone (ADH). The person with water deprivation will have a high plasma osmolarity, and the person with syndrome of inappropriate antidiuretic hormone (SIADH) will have a low plasma osmolarity (because of dilution by the inappropriate water reabsorption).

20. The answer is B [Table 5-11]. Thiazide diuretics have a unique effect on the distal tubule; they increase Ca2+ reabsorption, thereby decreasing Ca2+ excretion and clearance. Because parathyroid hormone (PTH) increases Ca2+ reabsorption, the lack of PTH will cause an increase in Ca2+ clearance. Furosemide inhibits Na+ reabsorption in the thick ascending limb, and extracellular fluid (ECF) volume expansion inhibits Na+ reabsorption in the proximal tubule. At these sites, Ca2+ reabsorption is linked to Na+ reabsorption, and Ca2+ clearance would be increased. Because Mg2+ competes with Ca2+ for reabsorption in the thick ascending limb, hypermagnesemia will cause increased Ca2+ clearance.

21. The answer is D [IX D 2; Table 5-8]. First, the acid–base disorder must be diagnosed. Alkaline pH, with increased HCO3– and increased PCO2, is consistent with metabolic alkalosis with respiratory compensation. The low blood pressure and decreased turgor suggest extracellular fluid (ECF) volume contraction. The reduced [H+] in blood will cause intracellular H+ to leave cells in exchange for extracellular K+. The appropriate respiratory compensation is hypoventilation, which is responsible for the elevated PCO2. H+ excretion in urine will be decreased, so less titratable acid will be excreted. K+ secretion by the distal tubules will be increased because aldosterone levels will be increased secondary to ECF volume contraction.

22. The answer is B [VII B; Figure 5-14]. This patient’s plasma and urine osmolarity, taken together, are consistent with water deprivation. The plasma osmolarity is on the high side of normal, stimulating the posterior pituitary to secrete antidiuretic hormone (ADH). Secretion of ADH, in turn, acts on the collecting ducts to increase water reabsorption and produce hyperosmotic urine. Syndrome of inappropriate antidiuretic hormone (SIADH) would also produce hyperosmotic urine, but the plasma osmolarity would be lower than normal because of the excessive water retention. Central and nephrogenic diabetes insipidus and excessive water intake would all result in hyposmotic urine.

23. The answer is C [II B 2, 3]. Effective renal plasma flow (RPF) is calculated from the clearance of para-aminohippuric acid (PAH) [CPAH = UPAH × V/PPAH = 600 mL/min]. Renal blood flow (RBF) = RPF/1 – hematocrit = 1091 mL/min.

24. The answer is A [III D]. Para-aminohippuric acid (PAH) has the greatest clearance of all of the substances because it is both filtered and secreted. Inulin is only filtered. The other substances are filtered and subsequently reabsorbed; therefore, they will have clearances that are lower than the inulin clearance.


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25. The answer is D [I C 2 f; Table 5-2]. By sweating and then replacing all volume by drinking H2O, the woman has a net loss of NaCl without a net loss of H2O. Therefore, her extracellular and plasma osmolarity will be decreased, and as a result, water will flow from extracellular fluid (ECF) to intracellular fluid (ICF). The intracellular osmolarity will also be decreased after the shift of water. Total body water (TBW) will be unchanged because the woman replaced all volume lost in sweat by drinking water. Hematocrit will be increased because of the shift of water from ECF to ICF and the shift of water into the red blood cells (RBCs), which causes their volume to increase.

26. The answer is A [Table 5-4]. Exercise causes a shift of K+ from cells into blood. The result

is hyperkalemia. Hyposmolarity, insulin, β-agonists, and alkalosis cause a shift of K+ from blood into cells. The result is hypokalemia.

27. The answer is E [Table 5-9]. A cause of metabolic alkalosis is hyperaldosteronism;

increased aldosterone levels cause increased H+ secretion by the distal tubule and increased reabsorption of “new” HCO3–. Diarrhea causes loss of HCO3– from the gastrointestinal (GI) tract and acetazolamide causes loss of HCO3– in the urine, both resulting in hyperchloremic metabolic acidosis with normal anion gap. Ingestion of ethylene glycol and salicylate poisoning leads to metabolic acidosis with increased anion gap.

28. The answer is A [VI B; Table 5-7]. Parathyroid hormone (PTH) acts on the renal tubule by stimulating adenyl cyclase and generating cyclic adenosine monophosphate (cAMP). The major actions of the hormone are inhibition of phosphate reabsorption in the proximal tubule, stimulation of Ca2+ reabsorption in the distal tubule, and stimulation of 1,25-dihydroxycholecalciferol production. PTH does not alter the renal handling of K+.

29. The answer is C [IV C 3 b; V B 4 b]. Hypertension, hypokalemia, metabolic alkalosis, elevated serum aldosterone, and decreased plasma renin activity are all consistent with a primary hyperaldosteronism (e.g., Conn’s syndrome). High levels of aldosterone cause increased Na+ reabsorption (leading to increased blood pressure), increased K+ secretion (leading to hypokalemia), and increased H+ secretion (leading to metabolic alkalosis). In Conn’s syndrome, the increased blood pressure causes an increase in renal perfusion pressure, which inhibits renin secretion. Neither Cushing’s syndrome nor Cushing’s disease is a possible cause of this patient’s hypertension because serum cortisol and adrenocorticotropic hormone (ACTH) levels are normal. Renal artery stenosis causes hypertension that is characterized by increased plasma renin activity. Pheochromocytoma is ruled out by the normal urinary excretion of vanillylmandelic acid (VMA).

30. The answer is D [IX D 3; Tables 5-8 and 5-9]. The history strongly suggests chronic obstructive pulmonary disease (COPD) as a cause of respiratory acidosis. Because of the COPD, the ventilation rate is decreased and CO2 is retained. The [H+] and [HCO3–] are increased by mass action. The [HCO3–] is further increased by renal compensation for respiratory acidosis (increased HCO3– reabsorption by the kidney is facilitated by the high PCO2).

31. The answer is B [IX D 4; Table 5-8]. The blood values in respiratory alkalosis show

decreased PCO2 (the cause) and decreased [H+] and [HCO3–] by mass action. The [HCO3–] is further decreased by renal compensation for chronic respiratory alkalosis (decreased HCO3– reabsorption).

32. The answer is E [IX D 1; Tables 5-8 and 5-9]. In patients who have chronic renal failure and ingest normal amounts of protein, fixed acids will be produced from the catabolism of protein. Because the failing kidney does not produce enough NH4+ to excrete all of the fixed acid, metabolic acidosis (with respiratory compensation) results.

33. The answer is E [IX D 1; Tables 5-8 and 5-9]. Untreated diabetes mellitus results in the production of ketoacids, which are fixed acids that cause metabolic acidosis. Urinary excretion of NH4+ is increased in this patient because an adaptive increase in renal NH3 synthesis has occurred in response to the metabolic acidosis.



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34. The answer is A [IX D 2; Tables 5-8 and 5-9]. The history of vomiting (in the absence of any other information) indicates loss of gastric H+ and, as a result, metabolic alkalosis (with respiratory compensation).

35. The answer is E [V B 4]. K+ is secreted by the late distal tubule and collecting ducts.

Because this secretion is affected by dietary K+, a person who is on a high-K+ diet can secrete more K+ into the urine than was originally filtered. At all of the other nephron sites, the amount of K+ in the tubular fluid is either equal to the amount filtered (site A) or less than the amount filtered (because K+ is reabsorbed in the proximal tubule and the loop of Henle).

36. The answer is D [VII B 3; Figure 5-16]. A person who is deprived of water will have high circulating levels of antidiuretic hormone (ADH). The tubular fluid/plasma (TF/P) osmolarity is 1.0 throughout the proximal tubule, regardless of ADH status. In antidiuresis, TF/P osmolarity > 1.0 at site C because of equilibration of the tubular fluid with the large corticopapillary osmotic gradient. At site E, TF/P osmolarity > 1.0 because of water reabsorption out of the collecting ducts and equilibration with the corticopapillary gradient. At site D, the tubular fluid is diluted because NaCl is reabsorbed in the thick ascending limb without water, making TF/P osmolarity < 1.0.

37. The answer is E [IV A 2]. Because inulin, once filtered, is neither reabsorbed nor secreted, its concentration in tubular fluid reflects the amount of water remaining in the tubule. In antidiuresis, water is reabsorbed throughout the nephron (except in the thick ascending limb and cortical diluting segment). Thus, inulin concentration in the tubular fluid progressively rises along the nephron as water is reabsorbed, and will be highest in the final urine.

38. The answer is A [IV A 2]. The tubular fluid inulin concentration depends on the amount of water present. As water reabsorption occurs along the nephron, the inulin concentration progressively increases. Thus, the tubular fluid inulin concentration is lowest in Bowman’s space, prior to any water reabsorption.

39. The answer is A [IV C 1 a]. Glucose is extensively reabsorbed in the early proximal tubule

by the Na+–glucose cotransporter. The glucose concentration in tubular fluid is highest in Bowman’s space before any reabsorption has occurred.

40. The answer is C [IV A 2]. Once inulin is filtered, it is neither reabsorbed nor secreted. Thus, 100% of the filtered inulin remains in tubular fluid at each nephron site and in the final urine.

41. The answer is A [IV C 1 a]. Alanine, like glucose, is avidly reabsorbed in the early proximal

tubule by a Na+–amino acid cotransporter. Thus, the percentage of the filtered load of alanine remaining in the tubular fluid declines rapidly along the proximal tubule as alanine is reabsorbed into the blood.

42. The answer is D [III C; IV A 3]. Para-aminohippuric acid (PAH) is an organic acid that is filtered and subsequently secreted by the proximal tubule. The secretion process adds PAH to the tubular fluid; therefore, the amount that is present at the end of the proximal tubule is greater than the amount that was present in Bowman’s space.

43. The answer is B [III E]. Alkalinization of the urine converts more salicylic acid to its A– form. The A– form is charged and cannot back-diffuse from urine to blood. Therefore, it is trapped in the urine and excreted.

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chapter

6

Gastrointestinal Physiology

I. STRUCTURE AND INNERVATION OF THE GASTROINTESTINAL TRACT A. Structure of the gastrointestinal (GI) tract (Figure 6-1) 1. Epithelial cells ■

are specialized in different parts of the GI tract for secretion or absorption.

2. Muscularis mucosa ■

Contraction causes a change in the surface area for secretion or absorption.

3. Circular muscle ■

Contraction causes a decrease in diameter of the lumen of the GI tract.

4. Longitudinal muscle ■

Contraction causes shortening of a segment of the GI tract.

5. Submucosal plexus (Meissner’s plexus) and myenteric plexus ■ ■

comprise the enteric nervous system of the GI tract. integrate and coordinate the motility, secretory, and endocrine functions of the GI tract.

B. Innervation of the GI tract ■

The autonomic nervous system (ANS) of the GI tract comprises both extrinsic and intrinsic nervous systems.

1. Extrinsic innervation (parasympathetic and sympathetic nervous systems) ■ ■

Efferent fibers carry information from the brain stem and spinal cord to the GI tract. Afferent fibers carry sensory information from chemoreceptors and mechanoreceptors in the GI tract to the brain stem and spinal cord.

a. Parasympathetic nervous system ■ ■ ■ ■

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is usually excitatory on the functions of the GI tract. is carried via the vagus and pelvic nerves. Preganglionic parasympathetic fibers synapse in the myenteric and submucosal plexuses. Cell bodies in the ganglia of the plexuses then send information to the smooth muscle, secretory cells, and endocrine cells of the GI tract.

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Epithelial cells, endocrine cells, and receptor cells

Lamina propria Muscularis mucosae Submucosal plexus Circular muscle Myenteric plexus

Longitudinal muscle Serosa

FIGURE 6-1 Structure of the gastrointestinal tract.

(1) The vagus nerve innervates the esophagus, stomach, pancreas, and upper large intestine. ■

Reflexes in which both afferent and efferent pathways are contained in the vagus nerve are called vagovagal reflexes.

(2) The pelvic nerve innervates the lower large intestine, rectum, and anus. b. Sympathetic nervous system ■ ■ ■ ■

■

is usually inhibitory on the functions of the GI tract. Fibers originate in the spinal cord between T-8 and L-2. Preganglionic sympathetic cholinergic fibers synapse in the prevertebral ganglia. Postganglionic sympathetic adrenergic fibers leave the prevertebral ganglia and synapse in the myenteric and submucosal plexuses. Direct postganglionic adrenergic innervation of blood vessels and some smooth muscle cells also occurs. Cell bodies in the ganglia of the plexuses then send information to the smooth muscle, secretory cells, and endocrine cells of the GI tract.

2. Intrinsic innervation (enteric nervous system) ■ ■ ■

coordinates and relays information from the parasympathetic and sympathetic nervous systems to the GI tract. uses local reflexes to relay information within the GI tract. controls most functions of the GI tract, especially motility and secretion, even in the absence of extrinsic innervation.

a. Myenteric plexus (Auerbach’s plexus) ■

primarily controls the motility of the GI smooth muscle.

b. Submucosal plexus (Meissner’s plexus) ■ ■

primarily controls secretion and blood flow. receives sensory information from chemoreceptors and mechanoreceptors in the GI tract.

II. REGULATORY SUBSTANCES IN THE GASTROINTESTINAL TRACT (FIGURE 6-2) A. GI hormones (Table 6-1) ■

are released from endocrine cells in the GI mucosa into the portal circulation, enter the general circulation, and have physiologic actions on target cells.

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Board Review Series: Physiology Hormones

Paracrines

Neurocrines

Endocrine cell

Endocrine cell

Neuron

Secretion

Action potential

Diffusion

Portal circulation Target cell

Target cell

Systemic circulation

Target cell FIGURE 6-2 Gastrointestinal hormones, paracrines, and neurocrines. ■

Four substances meet the requirements to be considered “official” GI hormones; others are considered “candidate” hormones. The four official GI hormones are gastrin, cholecystokinin (CCK), secretin, and glucose-dependent insulinotropic peptide (GIP).

1. Gastrin ■ ■ ■ ■

contains 17 amino acids (“little gastrin”). Little gastrin is the form secreted in response to a meal. All of the biologic activity of gastrin resides in the four C-terminal amino acids. “Big gastrin” contains 34 amino acids, although it is not a dimer of little gastrin.

t a b l e

6-1

Summary of Gastrointestinal (GI) Hormones

Hormones

Homology (Family)

Site of Secretion


Actions

Gastrin

Gastrin–CCK

G cells of stomach

↑ Gastric H+ secretion Stimulates growth of gastric mucosa

CCK

Gastrin–CCK

I cells of duodenum and jejunum

Small peptides and amino acids Distention of stomach Vagus (via GRP) Inhibited by H+ in stomach Inhibited by somatostatin Small peptides and amino acids Fatty acids

Secretin

Secretin–glucagon

S cells of duodenum

H+ in duodenum Fatty acids in duodenum

GIP

Secretin–glucagon

Duodenum and jejunum

Fatty acids, amino acids, and oral glucose

CCK = cholecystokinin; GIP = glucose-dependent insulinotropic peptide; GRP = gastrin-releasing peptide.

Stimulates contraction of gallbladder and relaxation of sphincter of Oddi ↑ Pancreatic enzyme and HCO3– secretion ↑ Growth of exocrine pancreas/gallbladder Inhibits gastric emptying ↑ Pancreatic HCO3– secretion ↑ Biliary HCO3– secretion ↓ Gastric H+ secretion ↑ Insulin secretion ↓ Gastric H+ secretion

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a. Actions of gastrin (1) Increases H+ secretion by the gastric parietal cells. (2) Stimulates growth of gastric mucosa by stimulating the synthesis of RNA and new protein. Patients with gastrin-secreting tumors have hypertrophy and hyperplasia of the gastric mucosa.

b. Stimuli for secretion of gastrin ■ ■

Gastrin is secreted from the G cells of the gastric antrum in response to a meal. Gastrin is secreted in response to the following:

(1) Small peptides and amino acids in the lumen of the stomach ■

The most potent stimuli for gastrin secretion are phenylalanine and tryptophan.

(2) Distention of the stomach (3) Vagal stimulation, mediated by gastrin-releasing peptide (GRP) ■

Atropine does not block vagally mediated gastrin secretion because the mediator of the vagal effect is GRP, not acetylcholine (ACh).

c. Inhibition of gastrin secretion ■

■

H+ in the lumen of the stomach inhibits gastrin release. This negative feedback control ensures that gastrin secretion is inhibited if the stomach contents are sufficiently acidified. Somatostatin inhibits gastrin release.

d. Zollinger–Ellison syndrome (gastrinoma) ■

occurs when gastrin is secreted by non–β-cell tumors of the pancreas.

2. CCK ■ ■ ■ ■

contains 33 amino acids. is homologous to gastrin. The five C-terminal amino acids are the same in CCK and gastrin. The biologic activity of CCK resides in the C-terminal heptapeptide. Thus, the heptapeptide contains the sequence that is homologous to gastrin and has gastrin activity as well as CCK activity.

a. Actions of CCK (1) Stimulates contraction of the gallbladder and simultaneously causes relaxation of the sphincter of Oddi for secretion of bile. (2) Stimulates pancreatic enzyme secretion. (3) Potentiates secretin-induced stimulation of pancreatic HCO3– secretion. (4) Stimulates growth of the exocrine pancreas. (5) Inhibits gastric emptying. Thus, meals containing fat stimulate the secretion of CCK, which slows gastric emptying to allow more time for intestinal digestion and absorption.

b. Stimuli for the release of CCK ■

CCK is released from the I cells of the duodenal and jejunal mucosa by:

(1) Small peptides and amino acids (2) Fatty acids and monoglycerides ■

Triglycerides do not stimulate the release of CCK because they cannot cross intestinal cell membranes.

3. Secretin ■ ■

contains 27 amino acids. is homologous to glucagon; 14 of the 27 amino acids in secretin are the same as those in glucagon.

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All of the amino acids are required for biologic activity.

a. Actions of secretin ■

are coordinated to reduce the amount of H+ in the lumen of the small intestine.

(1) Stimulates pancreatic HCO3– secretion and increases growth of the exocrine pancreas. Pancreatic HCO3– neutralizes H+ in the intestinal lumen. (2) Stimulates HCO3– and H2O secretion by the liver, and increases bile production. (3) Inhibits H+ secretion by gastric parietal cells. b. Stimuli for the release of secretin ■

Secretin is released by the S cells of the duodenum in response to:

(1) H+ in the lumen of the duodenum. (2) Fatty acids in the lumen of the duodenum. 4. GIP ■ ■

contains 42 amino acids. is homologous to secretin and glucagon.

a. Actions of GIP (1) Stimulates insulin release. In the presence of an oral glucose load, GIP causes the release of insulin from the pancreas. Thus, oral glucose is more effective than intravenous glucose in causing insulin release and, therefore, glucose utilization. (2) Inhibits H+ secretion by gastric parietal cells. b. Stimuli for the release of GIP ■ ■

GIP is secreted by the duodenum and jejunum. GIP is the only GI hormone that is released in response to fat, protein, and carbohydrate. GIP secretion is stimulated by fatty acids, amino acids, and orally administered glucose.

B. Paracrines ■ ■ ■

are released from endocrine cells in the GI mucosa. diffuse over short distances to act on target cells located in the GI tract. The GI paracrines are somatostatin and histamine.

1. Somatostatin ■ ■ ■

is secreted by cells throughout the GI tract in response to H+ in the lumen. Its secretion is inhibited by vagal stimulation. inhibits the release of all GI hormones. inhibits gastric H+ secretion.

2. Histamine ■ ■

is secreted by mast cells of the gastric mucosa. increases gastric H+ secretion directly and by potentiating the effects of gastrin and vagal stimulation.

C. Neurocrines ■ ■ ■

are synthesized in neurons of the GI tract, moved by axonal transport down the axon, and released by action potentials in the nerves. Neurocrines then diffuse across the synaptic cleft to a target cell. The GI neurocrines are vasoactive intestinal peptide (VIP), GRP (bombesin), and enkephalins.

1. VIP ■ ■ ■

contains 28 amino acids and is homologous to secretin. is released from neurons in the mucosa and smooth muscle of the GI tract. produces relaxation of GI smooth muscle, including the lower esophageal sphincter.

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Chapter 6 Gastrointestinal Physiology ■ ■

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stimulates pancreatic HCO3– secretion and inhibits gastric H+ secretion. In these actions, it resembles secretin. is secreted by pancreatic islet cell tumors and is presumed to mediate pancreatic cholera.

2. GRP (bombesin) ■ ■

is released from vagus nerves that innervate the G cells. stimulates gastrin release from G cells.

3. Enkephalins (met-enkephalin and leu-enkephalin) ■ ■ ■

are secreted from nerves in the mucosa and smooth muscle of the GI tract. stimulate contraction of GI smooth muscle, particularly the lower esophageal, pyloric, and ileocecal sphincters. inhibit intestinal secretion of fluid and electrolytes. This action forms the basis for the usefulness of opiates in the treatment of diarrhea.

III. GASTROINTESTINAL MOTILITY ■

■ ■ ■ ■

Contractile tissue of the GI tract is almost exclusively unitary smooth muscle, with the exception of the pharynx, upper one-third of the esophagus, and external anal sphincter, all of which are striated muscle. Depolarization of circular muscle leads to contraction of a ring of smooth muscle and a decrease in diameter of that segment of the GI tract. Depolarization of longitudinal muscle leads to contraction in the longitudinal direction and a decrease in length of that segment of the GI tract. Phasic contractions occur in the esophagus, gastric antrum, and small intestine, which contract and relax periodically. Tonic contractions occur in the lower esophageal sphincter, orad stomach, and ileocecal and internal anal sphincters.

A. Slow waves (Figure 6-3) ■ ■ ■ ■

are oscillating membrane potentials inherent to the smooth muscle cells of some parts of the GI tract. occur spontaneously. originate in the interstitial cells of Cajal, which serve as the pacemaker for GI smooth muscle. are not action potentials, although they determine the pattern of action potentials and, therefore, the pattern of contraction.

1. Mechanism of slow wave production

Tension

Voltage

■

is the cyclic opening of Ca2+ channels (depolarization) followed by opening of K+ channels (repolarization).

Action potential “spikes” superimposed on slow waves Slow wave

Contraction

FIGURE 6-3 Gastrointestinal slow waves superimposed by action potentials. Action potentials produce subsequent contraction.

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■

Depolarization during each slow wave brings the membrane potential of smooth muscle cells closer to threshold and, therefore, increases the probability that action potentials will occur. Action potentials, produced on top of the background of slow waves, then initiate phasic contractions of the smooth muscle cells (see Chapter 1 VII B).

2. Frequency of slow waves ■ ■

■ ■

varies along the GI tract, but is constant and characteristic for each part of the GI tract. is not influenced by neural or hormonal input. In contrast, the frequency of the action potentials that occur on top of the slow waves is modified by neural and hormonal influences. sets the maximum frequency of contractions for each part of the GI tract. is lowest in the stomach (3 slow waves/min) and highest in the duodenum (12 slow waves/min).

B. Chewing, swallowing, and esophageal peristalsis 1. Chewing ■ ■

lubricates food by mixing it with saliva. decreases the size of food particles to facilitate swallowing and to begin the digestive process.

2. Swallowing ■ ■

The swallowing reflex is coordinated in the medulla. Fibers in the vagus and glossopharyngeal nerves carry information between the GI tract and the medulla. The following sequence of events is involved in swallowing:

a. The nasopharynx closes and, at the same time, breathing is inhibited. b. The laryngeal muscles contract to close the glottis and elevate the larynx. c. Peristalsis begins in the pharynx to propel the food bolus toward the esophagus. Simultaneously, the upper esophageal sphincter relaxes to permit the food bolus to enter the esophagus.

3. Esophageal motility ■ ■ ■

■

The esophagus propels the swallowed food into the stomach. Sphincters at either end of the esophagus prevent air from entering the upper esophagus and gastric acid from entering the lower esophagus. Because the esophagus is located in the thorax, intraesophageal pressure equals thoracic pressure, which is lower than atmospheric pressure. In fact, a balloon catheter placed in the esophagus can be used to measure intrathoracic pressure. The following sequence of events occurs as food moves into and down the esophagus:

a. As part of the swallowing reflex, the upper esophageal sphincter relaxes to permit swallowed food to enter the esophagus.

b. The upper esophageal sphincter then contracts so that food will not reflux into the pharynx.

c. A primary peristaltic contraction creates an area of high pressure behind the food bolus. The peristaltic contraction moves down the esophagus and propels the food bolus along. Gravity accelerates the movement. d. A secondary peristaltic contraction clears the esophagus of any remaining food. e. As the food bolus approaches the lower end of the esophagus, the lower esophageal sphincter relaxes. This relaxation is vagally mediated, and the neurotransmitter is VIP. f. The orad region of the stomach relaxes (“receptive relaxation”) to allow the food bolus to enter the stomach.

4. Clinical correlations of esophageal motility a. Gastroesophageal reflux (heartburn) may occur if the tone of the lower esophageal sphincter is decreased and gastric contents reflux into the esophagus.

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b. Achalasia may occur if the lower esophageal sphincter does not relax during swallowing and food accumulates in the esophagus.

C. Gastric motility ■ ■ ■ ■

The stomach has three layers of smooth muscle—the usual longitudinal and circular layers, and a third oblique layer. The stomach has three anatomic divisions—the fundus, body, and antrum. The orad region of the stomach includes the fundus and the proximal body. This region contains oxyntic glands and is responsible for receiving the ingested meal. The caudad region of the stomach includes the antrum and the distal body. This region is responsible for the contractions that mix food and propel it into the duodenum.

1. “Receptive relaxation” ■ ■ ■

is a vagovagal reflex that is initiated by distention of the stomach and is abolished by vagotomy. The orad region of the stomach relaxes to accommodate the ingested meal. CCK participates in “receptive relaxation” by increasing the distensibility of the orad stomach.

2. Mixing and digestion ■

The caudad region of the stomach contracts to mix the food with gastric secretions and begins the process of digestion. The size of food particles is reduced.

a. Slow waves in the caudad stomach occur at a frequency of 3–5 waves/min. They depolarize the smooth muscle cells.

b. If threshold is reached during the slow waves, action potentials are fired, followed by contraction. Thus, the frequency of slow waves sets the maximal frequency of contraction. c. A wave of contraction closes the distal antrum. Thus, as the caudad stomach contracts, food is propelled back into the stomach to be mixed (retropulsion). d. Gastric contractions are increased by vagal stimulation and decreased by sympathetic

stimulation. e. Even during fasting, contractions (the “migrating myoelectric complex”) occur at 90-minute intervals and clear the stomach of residual food. Motilin is the mediator of these contractions.

3. Gastric emptying ■

The caudad region of the stomach contracts to propel food into the duodenum.

a. The rate of gastric emptying is fastest when the stomach contents are isotonic. If the stomach contents are hypertonic or hypotonic, gastric emptying is slowed.

b. Fat inhibits gastric emptying (i.e., increases gastric emptying time) by stimulating the release of CCK. c. H+ in the duodenum inhibits gastric emptying via direct neural reflexes. H+ receptors in the duodenum relay information to the gastric smooth muscle via interneurons in the GI plexuses.

D. Small intestinal motility ■

■

■

The small intestine functions in the digestion and absorption of nutrients. The small intestine mixes nutrients with digestive enzymes, exposes the digested nutrients to the absorptive mucosa, and then propels any nonabsorbed material to the large intestine. As in the stomach, slow waves set the basic electrical rhythm, which occurs at a frequency of 12 waves/min. Action potentials occur on top of the slow waves and lead to contractions. Parasympathetic stimulation increases intestinal smooth muscle contraction; sympathetic stimulation decreases it.

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1. Segmentation contractions ■ ■

■

mix the intestinal contents. A section of small intestine contracts, sending the intestinal contents (chyme) in both orad and caudad directions. That section of small intestine then relaxes, and the contents move back into the segment. This back-and-forth movement produced by segmentation contractions causes mixing without any net forward movement of the chyme.

2. Peristaltic contractions ■ ■ ■

are highly coordinated and propel the chyme through the small intestine toward the large intestine. Ideally, peristalsis occurs after digestion and absorption have taken place. Contraction behind the bolus and, simultaneously, relaxation in front of the bolus cause the chyme to be propelled caudally. The peristaltic reflex is coordinated by the enteric nervous system.

3. Gastroileal reflex ■ ■

is mediated by the extrinsic ANS and possibly by gastrin. The presence of food in the stomach triggers increased peristalsis in the ileum and relaxation of the ileocecal sphincter. As a result, the intestinal contents are delivered to the large intestine.

E. Large intestinal motility ■ ■

Fecal material moves from the cecum to the colon (i.e., through the ascending, transverse, descending, and sigmoid colons), to the rectum, and then to the anal canal. Haustra, or saclike segments, appear after contractions of the large intestine.

1. Cecum and proximal colon ■

When the proximal colon is distended with fecal material, the ileocecal sphincter contracts to prevent reflux into the ileum.

a. Segmentation contractions in the proximal colon mix the contents and are responsible for the appearance of haustra.

b. Mass movements occur 1 to 3 times/day and cause the colonic contents to move distally for long distances (e.g., from the transverse colon to the sigmoid colon).

2. Distal colon ■

Because most colonic water absorption occurs in the proximal colon, fecal material in the distal colon becomes semisolid and moves slowly. Mass movements propel it into the rectum.

3. Rectum, anal canal, and defecation ■

The sequence of events for defecation is as follows:

a. As the rectum fills with fecal material, it contracts and the internal anal sphincter relaxes (rectosphincteric reflex). b. Once the rectum is filled to about 25% of its capacity, there is an urge to defecate. However, defecation is prevented because the external anal sphincter is tonically contracted. c. When it is convenient to defecate, the external anal sphincter is relaxed voluntarily. The smooth muscle of the rectum contracts, forcing the feces out of the body. ■

Intra-abdominal pressure is increased by expiring against a closed glottis (Valsalva maneuver).

4. Gastrocolic reflex ■

The presence of food in the stomach increases the motility of the colon and increases the frequency of mass movements.

a. The gastrocolic reflex has a rapid parasympathetic component that is initiated when the stomach is stretched by food.

b. A slower, hormonal component is mediated by CCK and gastrin.

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5. Disorders of large intestinal motility a. Emotional factors strongly influence large intestinal motility via the extrinsic ANS. Irritable bowel syndrome may occur during periods of stress and may result in constipation (increased segmentation contractions) or diarrhea (decreased segmentation contractions).

b. Megacolon (Hirschsprung’s disease), the absence of the colonic enteric nervous system, results in constriction of the involved segment, marked dilatation and accumulation of intestinal contents proximal to the constriction, and severe constipation.

F. Vomiting ■ ■

■ ■

A wave of reverse peristalsis begins in the small intestine, moving the GI contents in the orad direction. The gastric contents are eventually pushed into the esophagus. If the upper esophageal sphincter remains closed, retching occurs. If the pressure in the esophagus becomes high enough to open the upper esophageal sphincter, vomiting occurs. The vomiting center in the medulla is stimulated by tickling the back of the throat, gastric distention, and vestibular stimulation (motion sickness). The chemoreceptor trigger zone in the fourth ventricle is activated by emetics, radiation, and vestibular stimulation.

IV. GASTROINTESTINAL SECRETION (TABLE 6-2) A. Salivary secretion 1. Functions of saliva a. Initial starch digestion by α-amylase (ptyalin) and initial triglyceride digestion by lingual lipase t a b l e

6-2

Summary of Gastrointestinal (GI) Secretions

GI Secretion

Major Characteristics

Stimulated By

Inhibited By

Saliva

High HCO3– High K+ Hypotonic α-Amylase Lingual lipase HCl

Parasympathetic nervous system Sympathetic nervous system

Sleep Dehydration Atropine

Gastrin Parasympathetic nervous system Histamine

↓ Stomach pH Chyme in duodenum (via secretin and GIP) Somatostatin Atropine Cimetidine Omeprazole

Gastric secretion

Pepsinogen

Parasympathetic nervous system

Intrinsic factor Pancreatic secretion

High HCO3– Isotonic

Secretin CCK (potentiates secretin) Parasympathetic nervous system

Bile

Pancreatic lipase, amylase, proteases Bile salts Bilirubin Phospholipids Cholesterol

CCK Parasympathetic nervous system CCK (causes contraction of gallbladder and relaxation of sphincter of Oddi) Parasympathetic nervous system (causes contraction of gallbladder)

CCK = cholecystokinin; GIP = gastric inhibitory peptide.

Ileal resection

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Board Review Series: Physiology Concentration relative to [plasma]

Concentration or osmolarity

Na+; osmolarity

plasma

–

HCO3 –

plasma

Flow rate of saliva FIGURE 6-4 Composition of saliva as a function of salivary flow rate.

b. Lubrication of ingested food by mucus c. Protection of the mouth and esophagus by dilution and buffering of ingested foods 2. Composition of saliva a. Saliva is characterized by: (1) High volume (relative to the small size of the salivary glands) (2) High K + and HCO3– concentrations (3) Low Na+ and Cl– concentrations (4) Hypotonicity (5) Presence of α-amylase, lingual lipase, and kallikrein b. The composition of saliva varies with the salivary flow rate (Figure 6-4). (1) At the lowest flow rates, saliva has the lowest osmolarity and lowest Na+, Cl–, and

HCO3– concentrations, but has the highest K+ concentration. (2) At the highest flow rates (up to 4 mL/min), the composition of saliva is closest to that of plasma. 3. Formation of saliva (Figure 6-5) ■ ■

■

Saliva is formed by three major glands—the parotid, submandibular, and sublingual glands. The structure of each gland is similar to a bunch of grapes. The acinus (the blind end of each duct) is lined with acinar cells and secretes an initial saliva. A branching duct system is lined with columnar epithelial cells, which modify the initial saliva. When saliva production is stimulated, myoepithelial cells, which line the acinus and initial ducts, contract and eject saliva into the mouth.

a. The acinus ■ ■

produces an initial saliva with a composition similar to plasma. This initial saliva is isotonic and has the same Na+, K+, Cl–, and HCO3– concentrations as plasma.

Na+

K+

Acinar cells Ductal cells Plasma-like solution (isotonic)

Saliva (hypotonic)

Cl– FIGURE 6-5 Modification of saliva by ductal cells.

HCO3–

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b. The ducts ■

modify the initial saliva by the following processes:

(1) The ducts reabsorb Na+ and Cl–; therefore, the concentrations of these ions are lower than their plasma concentrations.

(2) The ducts secrete K+ and HCO3–; therefore, the concentrations of these ions are higher than their plasma concentrations.

(3) Aldosterone acts on the ductal cells to increase the reabsorption of Na+ and the secretion of K+ (analogous to its actions on the renal distal tubule).

(4) Saliva becomes hypotonic in the ducts because the ducts are relatively impermeable to water. Because more solute than water is reabsorbed by the ducts, the saliva becomes dilute relative to plasma. (5) The effect of flow rate on saliva composition is explained primarily by changes in the contact time available for reabsorption and secretion processes to occur in the ducts. ■ ■ ■

Thus, at high flow rates, saliva is most like the initial secretion from the acinus; it has the highest Na+ and Cl– concentrations and the lowest K+ concentration. At low flow rates, saliva is least like the initial secretion from the acinus; it has the lowest Na+ and Cl– concentrations and the highest K+ concentration. The only ion that does not “fit” this contact-time explanation is HCO3–; HCO3– secretion is selectively stimulated when saliva secretion is stimulated.

4. Regulation of saliva production (Figure 6-6) ■ ■

Saliva production is controlled by the parasympathetic and sympathetic nervous systems (not by GI hormones). Saliva production is unique in that it is increased by both parasympathetic and sympathetic activity. Parasympathetic activity is more important, however.

Conditioning

Dehydration

Food

Fear

Nausea Smell

Sleep Anticholinergic drugs

Parasympathetic

Sympathetic

ACh

NE Atropine

β Receptor

Muscarinic receptor

Acinar and ductal cells IP3 , Ca2+

cAMP

Saliva FIGURE 6-6 Regulation of salivary secretion. ACh = acetylcholine; cAMP = cyclic adenosine monophosphate; IP3 = inositol 1,4,5-triphosphate; NE = norepinephrine.

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a. Parasympathetic stimulation (cranial nerves VII and IX) ■ ■ ■ ■

increases saliva production by increasing transport processes in the acinar and ductal cells and by causing vasodilation. Cholinergic receptors on acinar and ductal cells are muscarinic. The second messenger is inositol 1,4,5-triphosphate (IP3) and increased intracellular [Ca2+]. Anticholinergic drugs (e.g., atropine) inhibit the production of saliva and cause dry mouth.

b. Sympathetic stimulation ■ ■ ■

increases the production of saliva and the growth of salivary glands, although the effects are smaller than those of parasympathetic stimulation. Receptors on acinar and ductal cells are a-adrenergic. The second messenger is cyclic adenosine monophosphate (cAMP).

c. Saliva production ■ ■

is increased (via activation of the parasympathetic nervous system) by food in the mouth, smells, conditioned reflexes, and nausea. is decreased (via inhibition of the parasympathetic nervous system) by sleep, dehydration, fear, and anticholinergic drugs.

B. Gastric secretion 1. Gastric cell types and their secretions (Table 6-3 and Figure 6-7) ■ ■

Parietal cells, located in the body, secrete HCl and intrinsic factor. Chief cells, located in the body, secrete pepsinogen. ■ G cells, located in the antrum, secrete gastrin.

2. Mechanism of gastric H+ secretion (Figure 6-8) ■

Parietal cells secrete HCl into the lumen of the stomach and, concurrently, absorb HCO3– into the bloodstream as follows:

a. In the parietal cells, CO2 and H2O are converted to H+ and HCO3–, catalyzed by carbonic anhydrase. b. H+ is secreted into the lumen of the stomach by the H+–K+ pump (H+,K+-ATPase). Cl– is secreted along with H+; thus, the secretion product of the parietal cells is HCl.

■

The drug omeprazole (a “proton pump inhibitor”) inhibits the H+,K+-ATPase and blocks H+ secretion.

c. The HCO3– produced in the cells is absorbed into the bloodstream in exchange for Cl– (Cl––HCO3– exchange). As HCO3– is added to the venous blood, the pH of the t a b l e

6-3

Gastric Cell Types and their Secretions

Cell Type

Part of Stomach

Secretion Products


Parietal cells

Body (fundus)

HCl

Gastrin Vagal stimulation (ACh) Histamine

Chief cells

Body (fundus)

G cells

Antrum

Mucous cells

Antrum

ACh = acetylcholine; GRP = gastrin-releasing peptide.

Intrinsic factor (essential) Pepsinogen (converted to pepsin at low pH) Gastrin

Mucus Pepsinogen

Vagal stimulation (ACh) Vagal stimulation (via GRP) Small peptides Inhibited by somatostatin Inhibited by H+ in stomach (via stimulation of somatostatin release) Vagal stimulation (ACh)

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Fundus

Intrinsic factor Parietal cells

+ HCl Body

Pepsinogen Chief cells

G cells Gastrin Antrum FIGURE 6-7 Gastric cell types and their functions.

blood increases (“alkaline tide”). (Eventually, this HCO3– will be secreted in pancreatic secretions to neutralize H+ in the small intestine.) ■

If vomiting occurs, gastric H+ never arrives in the small intestine, there is no stimulus for pancreatic HCO3– secretion, and the arterial blood becomes alkaline (metabolic alkalosis).

3. Stimulation of gastric H+ secretion (Figure 6-9)

a. Vagal stimulation ■ ■

■

■

increases H+ secretion by a direct pathway and an indirect pathway. In the direct path, the vagus nerve innervates parietal cells and stimulates H+ secretion directly. The neurotransmitter at these synapses is ACh, the receptor on the parietal cells is muscarinic (M3), and the second messengers for CCK are IP3 and increased intracellular [Ca2+]. In the indirect path, the vagus nerve innervates G cells and stimulates gastrin secretion, which then stimulates H+ secretion by an endocrine action. The neurotransmitter at these synapses is GRP (not ACh). Atropine, a cholinergic muscarinic antagonist, inhibits H+ secretion by blocking the direct pathway, which uses ACh as a neurotransmitter. However, atropine does not Lumen of stomach

Gastric parietal cell Cl–

HCl

H+ K+

Blood Cl–

H+ + HCO3– H2CO3 CA

HCO3– (“alkaline tide”) Na+ K+

CO2 + H2O FIGURE 6-8 Simplified mechanism of H+ secretion by gastric parietal cells. CA = carbonic anhydrase.

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Board Review Series: Physiology Vagus

G cells

ECL cells

ACh

Gastrin

Histamine

Prostaglandins

Cimetidine

Atropine M3 receptor

Somatostatin

CCKB receptor

H2 receptor

Gq

Gs

Gi +

IP3 /Ca2+

Gastric parietal cell

– cAMP

+

+

H+,K+-ATPase

Lumen Omeprazole H+ secretion FIGURE 6-9 Agents that stimulate and inhibit secretion by gastric parietal cells. ACh = acetylcholine; cAMP = cyclic adenosine monophosphate; CCK = cholecystokinin; ECL = enterochromaffin-like; IP3 = inositol 1, 4, 5-triphosphate; M = muscarinic.

H+

■

block H+ secretion completely because it does not inhibit the indirect pathway, which uses GRP as a neurotransmitter. Vagotomy eliminates both direct and indirect pathways.

b. Gastrin ■ ■ ■

is released in response to eating a meal (small peptides, distention of the stomach, vagal stimulation). stimulates H+ secretion by interacting with the cholecystokininB (CCKB) receptor on the parietal cells. The second messenger for gastrin on the parietal cell is IP3/Ca2+.

c. Histamine ■ ■ ■ ■ ■

is released from enterochromaffin-like (ECL) cells in the gastric mucosa and diffuses to the nearby parietal cells. stimulates H+ secretion by activating H2 receptors on the parietal cell membrane. The H2 receptor is coupled to adenylyl cyclase via a Gs protein. The second messenger for histamine is cAMP. H2 receptor–blocking drugs, such as cimetidine, inhibit H+ secretion by blocking the stimulatory effect of histamine.

d. Potentiating effects of ACh, histamine, and gastrin on H+ secretion ■

■

Potentiation occurs when the response to simultaneous administration of two stimulants is greater than the sum of responses to either agent given alone. As a result, low concentrations of stimulants given together can produce maximal effects. Potentiation of gastric H+ secretion can be explained, in part, because each agent has a different mechanism of action on the parietal cell.

(1) Histamine potentiates the actions of ACh and gastrin in stimulating H+ secretion.

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Chapter 6 Gastrointestinal Physiology ■

205

Thus, H2 receptor blockers (e.g., cimetidine) are particularly effective in treating ulcers because they block both the direct action of histamine on parietal cells and the potentiating effects of histamine on ACh and gastrin.

(2) ACh potentiates the actions of histamine and gastrin in stimulating H+ secretion. ■

Thus, muscarinic receptor blockers, such as atropine, block both the direct action of ACh on parietal cells and the potentiating effects of ACh on histamine and gastrin.

4. Inhibition of gastric H+ secretion ■

Negative feedback mechanisms inhibit the secretion of H+ by the parietal cells.

a. Low pH (< 3.0) in the stomach ■ ■

inhibits gastrin secretion and thereby inhibits H+ secretion.

After a meal is ingested, H+ secretion is stimulated by the mechanisms discussed previously (see IV B 2). After the meal is digested and the stomach emptied, further H+ secretion decreases the pH of the stomach contents. When the pH of the stomach contents is plasma

Cl

< plasma

K+

~ plasma

–

Flow rate of pancreatic juice FIGURE 6-10 Composition of pancreatic secretion as a function of pancreatic flow rate.

a. Acinar cells ■

produce a small volume of initial pancreatic secretion, which is mainly Na+ and Cl–.

b. Ductal cells ■

modify the initial pancreatic secretion by secreting HCO3– and absorbing Cl– via a Cl––HCO3– exchange mechanism in the luminal membrane.

■

Because the pancreatic ducts are permeable to water, H2O moves into the lumen to make the pancreatic secretion isosmotic.

3. Stimulation of pancreatic secretion a. Secretin ■ ■ ■

■

is secreted by the S cells of the duodenum in response to H+ in the duodenal lumen. acts on the pancreatic ductal cells to increase HCO3– secretion. Thus, when H+ is delivered from the stomach to the duodenum, secretin is released. As a result, HCO3– is secreted from the pancreas into the duodenal lumen to neutralize the H+. The second messenger for secretin is cAMP.

b. CCK ■ ■ ■ ■

is secreted by the I cells of the duodenum in response to small peptides, amino acids, and fatty acids in the duodenal lumen. acts on the pancreatic acinar cells to increase enzyme secretion (amylase, lipases, proteases). potentiates the effect of secretin on ductal cells to stimulate HCO3– secretion. The second messengers for CCK are IP3 and increased intracellular [Ca2+]. The potentiating effects of CCK on secretin are explained by the different mechanisms of action for the two GI hormones (i.e., cAMP for secretin and IP3/Ca2+ for CCK). Lumen of duct

Pancreatic ductal cell

Blood

Cl– HCO3–

HCO3– + H+

H+ Na+

H2CO3 CA FIGURE 6-11 Modification of pancreatic secretion by ductal cells. CA = carbonic anhydrase.

Na+ K+

CO2 + H2O Na+

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c. ACh (via vagovagal reflexes) ■ ■

is released in response to H+, small peptides, amino acids, and fatty acids in the duodenal lumen. stimulates enzyme secretion by the acinar cells and, like CCK, potentiates the effect of secretin on HCO3– secretion.

4. Cystic fibrosis ■ ■ ■

is a disorder of pancreatic secretion. results from a defect in Cl– channels that is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. is associated with a deficiency of pancreatic enzymes resulting in malabsorption and steatorrhea.

D. Bile secretion and gallbladder function (Figure 6-12) 1. Composition and function of bile ■

Bile contains bile salts, phospholipids, cholesterol, and bile pigments (bilirubin).

a. Bile salts ■

■

are amphipathic molecules because they have both hydrophilic and hydrophobic portions. In aqueous solution, bile salts orient themselves around droplets of lipid and keep the lipid droplets dispersed (emulsification). aid in the intestinal digestion and absorption of lipids by emulsifying and solubilizing them in micelles.

b. Micelles ■ ■

■

Above a critical micellar concentration, bile salts form micelles. Bile salts are positioned on the outside of the micelle, with their hydrophilic portions dissolved in the aqueous solution of the intestinal lumen and their hydrophobic portions dissolved in the micelle interior. Free fatty acids and monoglycerides are present in the inside of the micelle, essentially “solubilized” for subsequent absorption.

2. Formation of bile ■ ■

Bile is produced continuously by hepatocytes. Bile drains into the hepatic ducts and is stored in the gallbladder for subsequent release. +

CCK

–

Gallbladder

Bile salts Sphincter of Oddi

Duodenum

Micelles Liver

Cholesterol

Bile salts

Bile salts Na+

FIGURE 6-12 Recirculation of bile acids from the ileum to the liver. CCK = cholecystokinin.

Ileum

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Chapter 6 Gastrointestinal Physiology ■ ■

209

Choleretic agents increase the formation of bile. Bile is formed by the following process:

a. Primary bile acids (cholic acid and chenodeoxycholic acid) are synthesized from cholesterol by hepatocytes. ■ ■

In the intestine, bacteria convert a portion of each of the primary bile acids to secondary bile acids (deoxycholic acid and lithocholic acid). Synthesis of new bile acids occurs, as needed, to replace bile acids that are excreted in the feces.

b. The bile acids are conjugated with glycine or taurine to form their respective bile salts, which are named for the parent bile acid (e.g., taurocholic acid is cholic acid conjugated with taurine). c. Electrolytes and H2O are added to the bile. d. During the interdigestive period, the gallbladder is relaxed, the sphincter of Oddi is closed, and the gallbladder fills with bile. e. Bile is concentrated in the gallbladder as a result of isosmotic absorption of solutes and H2O.

3. Contraction of the gallbladder a. CCK ■ ■ ■

is released in response to small peptides and fatty acids in the duodenum. tells the gallbladder that bile is needed to emulsify and absorb lipids in the duodenum. causes contraction of the gallbladder and relaxation of the sphincter of Oddi.

b. ACh ■

causes contraction of the gallbladder.

4. Recirculation of bile acids to the liver ■ ■ ■

The terminal ileum contains a Na+–bile acid cotransporter, which is a secondary active transporter that recirculates bile acids to the liver. Because bile acids are not recirculated until they reach the terminal ileum, bile acids are present for maximal absorption of lipids throughout the upper small intestine. After ileal resection, bile acids are not recirculated to the liver, but are excreted in feces. The bile acid pool is thereby depleted and fat absorption is impaired, resulting in steatorrhea.

V. DIGESTION AND ABSORPTION (TABLE 6-4) ■ ■

Carbohydrates, proteins, and lipids are digested and absorbed in the small intestine. The surface area for absorption in the small intestine is greatly increased by the presence of the brush border.

A. Carbohydrates 1. Digestion of carbohydrates ■

Only monosaccharides are absorbed. Carbohydrates must be digested to glucose, galactose, and fructose for absorption to proceed.

a. `-Amylases (salivary and pancreatic) hydrolyze 1,4-glycosidic bonds in starch, yielding maltose, maltotriose, and α-limit dextrins.

b. Maltase, `-dextrinase, and sucrase in the intestinal brush border then hydrolyze the oligosaccharides to glucose.

c. Lactase, trehalase, and sucrase degrade their respective disaccharides to monosaccharides.

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t a b l e

6-4

Summary of Digestion and Absorption

Nutrient

Digestion

Site of Absorption

Carbohydrates

To monosaccharides Small intestine (glucose, galactose, fructose)

Proteins

To amino acids, dipeptides, tripeptides

Lipids

To fatty acids, monoglycerides, cholesterol

Fat-soluble vitamins Water-soluble vitamins Vitamin B12 Bile acids Ca2+ Fe2+

Fe3+ is reduced to Fe2+

■ ■ ■

Mechanism of Absorption

Na+-dependent cotransport (glucose, galactose) Facilitated diffusion (fructose) Small intestine Na+-dependent cotransport (amino acids) H+-dependent cotransport (di- and tripeptides) Small intestine Micelles form with bile salts in intestinal lumen Diffusion of fatty acids, monoglycerides, and cholesterol into cell Re-esterification in cell to triglycerides and phospholipids Chylomicrons form in cell (requires apoprotein) and are transferred to lymph Small intestine Micelles with bile salts Small intestine Na+-dependent cotransport Ileum of small intestine Intrinsic factor–vitamin B12 complex Ileum of small intestine Na+-dependent cotransport; recirculated to liver Small intestine Vitamin D–dependent (calbindin D-28K) Small intestine Binds to apoferritin in cell Circulates in blood bound to transferrin

Lactase degrades lactose to glucose and galactose. Trehalase degrades trehalose to glucose. Sucrase degrades sucrose to glucose and fructose.

2. Absorption of carbohydrates (Figure 6-13) a. Glucose and galactose ■

■ ■ ■

are transported from the intestinal lumen into the cells by a Na+-dependent cotransport (SGLT 1) in the luminal membrane. The sugar is transported “uphill” and Na+ is transported “downhill.” are then transported from cell to blood by facilitated diffusion (GLUT 2). The Na+–K+ pump in the basolateral membrane keeps the intracellular [Na+] low, thus maintaining the Na+ gradient across the luminal membrane. Poisoning the Na+–K+ pump inhibits glucose and galactose absorption by dissipating the Na+ gradient.

b. Fructose ■

is transported exclusively by facilitated diffusion; therefore, it cannot be absorbed against a concentration gradient. Lumen of intestine

Epithelial cell of small intestine

Blood Na+ K+

Glucose or galactose Secondary active

Na+

Glucose or galactose Facilitated diffusion

FIGURE 6-13 Mechanism of absorption of monosaccharides by intestinal epithelial cells. Glucose and galactose are absorbed by Na+-dependent cotransport (secondary active), and fructose (not shown) is absorbed by facilitated diffusion.

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3. Clinical disorders of carbohydrate absorption ■

Lactose intolerance results from the absence of brush border lactase and, thus, the inability to hydrolyze lactose to glucose and galactose for absorption. Nonabsorbed lactose and H2O remain in the lumen of the GI tract and cause osmotic diarrhea.

B. Proteins 1. Digestion of proteins a. Endopeptidases ■

degrade proteins by hydrolyzing interior peptide bonds.

b. Exopeptidases ■

hydrolyze one amino acid at a time from the C terminus of proteins and peptides.

c. Pepsin ■ ■ ■ ■ ■

is not essential for protein digestion. is secreted as pepsinogen by the chief cells of the stomach. Pepsinogen is activated to pepsin by gastric H+. The optimum pH for pepsin is between 1 and 3. When the pH is >5, pepsin is denatured. Thus, in the intestine, as HCO3– is secreted in pancreatic fluids, duodenal pH increases and pepsin is inactivated.

d. Pancreatic proteases ■ ■

include trypsin, chymotrypsin, elastase, carboxypeptidase A, and carboxypeptidase B. are secreted in inactive forms that are activated in the small intestine as follows:

(1) Trypsinogen is activated to trypsin by a brush border enzyme, enterokinase. (2) Trypsin then converts chymotrypsinogen, proelastase, and procarboxypeptidase A and B to their active forms. (Even trypsinogen is converted to more trypsin by trypsin!) (3) After their digestive work is complete, the pancreatic proteases degrade each other and are absorbed along with dietary proteins. 2. Absorption of proteins (Figure 6-14) ■

Digestive products of protein can be absorbed as amino acids, dipeptides, and tripeptides (in contrast to carbohydrates, which can only be absorbed as monosaccharides).

a. Free amino acids ■ ■ ■

Na+-dependent amino acid cotransport occurs in the luminal membrane. It is analogous to the cotransporter for glucose and galactose. The amino acids are then transported from cell to blood by facilitated diffusion. There are four separate carriers for neutral, acidic, basic, and imino amino acids, respectively.

Lumen of intestine

Epithelial cell of small intestine

Amino acids Na+ Dipeptides and tripeptides FIGURE 6-14 Mechanism of absorption of amino acids, dipeptides, and tripeptides by intestinal epithelial cells.

H+

Blood

Amino acids

peptidases

Na+ K+

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b. Dipeptides and tripeptides ■ ■ ■ ■

are absorbed faster than free amino acids. H+-dependent cotransport of dipeptides and tripeptides also occurs in the luminal membrane. After the dipeptides and tripeptides are transported into the intestinal cells, cytoplasmic peptidases hydrolyze them to amino acids. The amino acids are then transported from cell to blood by facilitated diffusion.

C. Lipids 1. Digestion of lipids a. Stomach (1) In the stomach, mixing breaks lipids into droplets to increase the surface area for digestion by pancreatic enzymes.

(2) Lingual lipases digest some of the ingested triglycerides to monoglycerides and fatty acids. However, most of the ingested lipids are digested in the intestine by pancreatic lipases. (3) CCK slows gastric emptying. Thus, delivery of lipids from the stomach to the duodenum is slowed to allow adequate time for digestion and absorption in the intestine.

b. Small intestine (1) Bile acids emulsify lipids in the small intestine, increasing the surface area for digestion.

(2) Pancreatic lipases hydrolyze lipids to fatty acids, monoglycerides, cholesterol, and lysolecithin. The enzymes are pancreatic lipase, cholesterol ester hydrolase, and phospholipase A2. (3) The hydrophobic products of lipid digestion are solubilized in micelles by bile

acids. 2. Absorption of lipids a. Micelles bring the products of lipid digestion into contact with the absorptive surface of the intestinal cells. Then, fatty acids, monoglycerides, and cholesterol diffuse across the luminal membrane into the cells. Glycerol is hydrophilic and is not contained in the micelles.

b. In the intestinal cells, the products of lipid digestion are re-esterified to triglycerides, cholesterol ester, and phospholipids and, with apoproteins, form chylomicrons. ■

Lack of apoprotein B results in the inability to transport chylomicrons out of the intestinal cells and causes abetalipoproteinemia.

c. Chylomicrons are transported out of the intestinal cells by exocytosis. Because chylomicrons are too large to enter the capillaries, they are transferred to lymph vessels and are added to the bloodstream via the thoracic duct.

3. Malabsorption of lipids—steatorrhea ■

can be caused by any of the following:

a. Pancreatic disease (e.g., pancreatitis, cystic fibrosis), in which the pancreas cannot

b. c. d.

e. f.

synthesize adequate amounts of the enzymes (e.g., pancreatic lipase) needed for lipid digestion. Hypersecretion of gastrin, in which gastric H+ secretion is increased and the duodenal pH is decreased. Low duodenal pH inactivates pancreatic lipase. Ileal resection, which leads to a depletion of the bile acid pool because the bile acids do not recirculate to the liver. Bacterial overgrowth, which may lead to deconjugation of bile acids and their “early” absorption in the upper small intestine. In this case, bile acids are not present throughout the small intestine to aid in lipid absorption. Decreased number of intestinal cells for lipid absorption (tropical sprue). Failure to synthesize apoprotein B, which leads to the inability to form chylomicrons.

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D. Absorption and secretion of electrolytes and H2O ■ ■ ■

Electrolytes and H2O may cross intestinal epithelial cells by either cellular or paracellular (between cells) routes. Tight junctions attach the epithelial cells to one another at the luminal membrane. The permeability of the tight junctions varies with the type of epithelium. A “tight” (impermeable) epithelium is the colon. “Leaky” (permeable) epithelia are the small intestine and gallbladder.

1. Absorption of NaCl a. Na+ moves into the intestinal cells, across the luminal membrane, and down its electrochemical gradient by the following mechanisms: (1) Passive diffusion (through Na+ channels) (2) Na+–glucose or Na+–amino acid cotransport (3) Na+–Cl– cotransport (4) Na+–H+ exchange ■

■

In the small intestine, Na+–glucose cotransport, Na+–amino acid cotransport, and Na+–H+ exchange mechanisms are most important. These cotransport and exchange mechanisms are similar to those in the renal proximal tubule. In the colon, passive diffusion via Na+ channels is most important. The Na+ channels of the colon are similar to those in the renal distal tubule and are stimulated by aldosterone.

b. Na+ is pumped out of the cell against its electrochemical gradient by the Na+–K+ pump in the basolateral membranes.

c. Cl– absorption accompanies Na+ absorption throughout the GI tract by the following mechanisms: (1) Passive diffusion by a paracellular route (2) Na+–Cl– cotransport (3) Cl––HCO3– exchange

2. Absorption and secretion of K+ a. Dietary K+ is absorbed in the small intestine by passive diffusion via a paracellular route.

b. K+ is actively secreted in the colon by a mechanism similar to that for K+ secretion in the renal distal tubule. ■ ■

As in the distal tubule, K+ secretion in the colon is stimulated by aldosterone. In diarrhea, K+ secretion by the colon is increased because of a flow rate– dependent mechanism similar to that in the renal distal tubule. Excessive loss of K+ in diarrheal fluid causes hypokalemia.

3. Absorption of H2O ■ ■ ■

is secondary to solute absorption. is isosmotic in the small intestine and gallbladder. The mechanism for coupling solute and water absorption in these epithelia is the same as that in the renal proximal tubule. In the colon, H2O permeability is much lower than in the small intestine, and feces may be hypertonic.

4. Secretion of electrolytes and H2O by the intestine ■ ■

The GI tract also secretes electrolytes from blood to lumen. The secretory mechanisms are located in the crypts. The absorptive mechanisms are located in the villi.

a. Cl– is the primary ion secreted into the intestinal lumen. It is transported through Cl– channels in the luminal membrane that are regulated by cAMP.

b. Na+ is secreted into the lumen by passively following Cl–. H2O follows NaCl to maintain isosmotic conditions.

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c. Vibrio cholerae (cholera toxin) causes diarrhea by stimulating Cl– secretion. ■ ■ ■ ■

Cholera toxin catalyzes adenosine diphosphate (ADP) ribosylation of the αs subunit of the Gs protein coupled to adenylyl cyclase, permanently activating it. Intracellular cAMP increases; as a result, Cl– channels in the luminal membrane open. Na+ and H2O follow Cl– into the lumen and lead to secretory diarrhea. Some strains of Escherichia coli cause diarrhea by a similar mechanism.

E. Absorption of other substances 1. Vitamins a. Fat-soluble vitamins (A, D, E, and K) are incorporated into micelles and absorbed along with other lipids.

b. Most water-soluble vitamins are absorbed by Na+-dependent cotransport mechanisms. c. Vitamin B12 is absorbed in the ileum and requires intrinsic factor. ■ ■

The vitamin B12–intrinsic factor complex binds to a receptor on the ileal cells and is absorbed. Gastrectomy results in the loss of gastric parietal cells, which are the source of intrinsic factor. Injection of vitamin B12 is required to prevent pernicious anemia.

2. Calcium ■

■

absorption in the small intestine depends on the presence of adequate amounts of the active form of vitamin D, 1,25-dihydroxycholecalciferol, which is produced in the kidney. 1,25-dihydroxycholecalciferol induces the synthesis of an intestinal Ca2+-binding protein, calbindin D-28K. Vitamin D deficiency or chronic renal failure results in inadequate intestinal Ca2+ absorption, causing rickets in children and osteomalacia in adults.

3. Iron ■

■

■

is absorbed as heme iron (iron bound to hemoglobin or myoglobin) or as free Fe2+. In the intestinal cells, “heme iron” is degraded and free Fe2+ is released. The free Fe2+ binds to apoferritin and is transported into the blood. Free Fe2+ circulates in the blood bound to transferrin, which transports it from the small intestine to its storage sites in the liver, and from the liver to the bone marrow for the synthesis of hemoglobin. Iron deficiency is the most common cause of anemia.

VI. LIVER PHYSIOLOGY A. Bile formation and secretion (see IV D) B. Bilirubin production and excretion (Figure 6-15) ■ ■ ■ ■ ■

Hemoglobin is degraded to bilirubin by the reticuloendothelial system. Bilirubin is carried in the circulation bound to albumin. In the liver, bilirubin is conjugated with glucuronic acid via the enzyme UDP glucuronyl transferase. A portion of conjugated bilirubin is excreted in the urine and a portion is secreted into bile. In the intestine, conjugated bilirubin is converted to urobilinogen, which is returned to the liver via the enterohepatic circulation, and urobilin and stercobilin, which are excreted in feces.

C. Metabolic functions of the liver 1. Carbohydrate metabolism ■

Performs gluconeogenesis, stores glucose as glycogen, and releases stored glucose into the circulation.

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Red blood cells

Hemoglobin Biliverdin

Reticuloendothelial system

Bilirubin

Bilirubin-albumin

Bloodstream

Bilirubin UDP glucuronyl transferase Excreted in urine

Enterohepatic circulation

Liver

Conjugated bilirubin


Bile


Small intestine

Urobilinogen

Terminal ileum

Urobilin Stercobilin

Colon

Excreted in feces FIGURE 6-15 Bilirubin metabolism. UDP, uridine diphosphate.

2. Protein metabolism ■ ■

Synthesizes nonessential amino acids Synthesizes plasma proteins

3. Lipid metabolism ■ ■

Participates in fatty acid oxidation Synthesizes lipoproteins, cholesterol, and phospholipids

D. Detoxification ■ ■ ■

Potentially toxic substances are presented to the liver via the portal circulation. Liver modifies these substances in “first pass metabolism.” Phase I reactions are catalyzed by cytochrome P-450 enzymes, which are followed by phase II reactions that conjugate the substances.

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Review Test 1. Which of the following substances is released from neurons in the GI tract and produces smooth muscle relaxation? (A) (B) (C) (D) (E)

Secretin Gastrin Cholecystokinin (CCK) Vasoactive intestinal peptide (VIP) Gastric inhibitory peptide (GIP)

2. Which of the following is the site of secretion of intrinsic factor?

(A) (B) (C) (D) (E)

Gastric antrum Gastric fundus Duodenum Ileum Colon

3. Vibrio cholerae causes diarrhea because it (A) increases HCO3– secretory channels in intestinal epithelial cells

(B) increases Cl– secretory channels in crypt cells

(C) prevents the absorption of glucose and causes water to be retained in the intestinal lumen isosmotically (D) inhibits cyclic adenosine monophosphate (cAMP) production in intestinal epithelial cells (E) inhibits inositol 1,4,5-triphosphate (IP3) production in intestinal epithelial cells

4. Cholecystokinin (CCK) has some gastrin-like properties because both CCK and gastrin

(A) are released from G cells in the stomach (B) are released from I cells in the

(C) Fructose (D) Alanine (E) Oligopeptides 6. A 49-year-old male patient with severe Crohn’s disease has been unresponsive to drug therapy and undergoes ileal resection. After the surgery, he will have steatorrhea because (A) the liver bile acid pool increases (B) chylomicrons do not form in the intestinal lumen

(C) micelles do not form in the intestinal lumen

(D) dietary triglycerides cannot be digested

(E) the pancreas does not secrete lipase 7. Cholecystokinin (CCK) inhibits (A) gastric emptying (B) pancreatic HCO3– secretion (C) pancreatic enzyme secretion (D) contraction of the gallbladder (E) relaxation of the sphincter of Oddi 8. Which of the following abolishes “receptive relaxation” of the stomach? (A) (B) (C) (D) (E)

Parasympathetic stimulation Sympathetic stimulation Vagotomy Administration of gastrin Administration of vasoactive intestinal peptide (VIP) (F) Administration of cholecystokinin (CCK)

duodenum (C) are members of the secretin-homologous family (D) have five identical C-terminal amino acids (E) have 90% homology of their amino acids

9. Secretion of which of the following

5. Which of the following is transported in intestinal epithelial cells by a Na+-dependent cotransport process?

10. Which of the following is the site of

(A) Fatty acids (B) Triglycerides

216

substances is inhibited by low pH?

(A) (B) (C) (D) (E)

Secretin Gastrin Cholecystokinin (CCK) Vasoactive intestinal peptide (VIP) Gastric inhibitory peptide (GIP)

secretion of gastrin?

(A) Gastric antrum (B) Gastric fundus (C) Duodenum

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(D) Ileum (E) Colon 11. Micelle formation is necessary for the intestinal absorption of

(A) (B) (C) (D) (E) (F)

glycerol galactose leucine bile acids vitamin B12 vitamin D

217

16. Which of the following substances must be further digested before it can be absorbed by specific carriers in intestinal cells?

(A) (B) (C) (D) (E)

Fructose Sucrose Alanine Dipeptides Tripeptides

17. Slow waves in small intestinal smooth muscle cells are

12. Which of the following changes occurs during defecation?

(A) (B) (C) (D)

Internal anal sphincter is relaxed External anal sphincter is contracted Rectal smooth muscle is relaxed Intra-abdominal pressure is lower than when at rest (E) Segmentation contractions predominate

(A) (B) (C) (D) (E)

action potentials phasic contractions tonic contractions oscillating resting membrane potentials oscillating release of cholecystokinin (CCK)

18. A 24-year-old male graduate student

of saliva?

participates in a clinical research study on intestinal motility. Peristalsis of the small intestine

(A) Hypotonicity relative to plasma (B) A lower HCO3– concentration than

(A) mixes the food bolus (B) is coordinated by the central nervous

(C) The presence of proteases (D) Secretion rate that is increased by

(C) involves contraction of smooth muscle

vagotomy (E) Modification by the salivary ductal cells involves reabsorption of K+ and HCO3–

(D) involves contraction of smooth muscle

13. Which of the following is characteristic

plasma

14. Which of the following substances is secreted in response to an oral glucose load? (A) (B) (C) (D) (E)

Secretin Gastrin Cholecystokinin (CCK) Vasoactive intestinal peptide (VIP) Glucose-dependent insulinotropic peptide (GIP)

15. Which of the following is true about the secretion from the exocrine pancreas?

(A) It has a higher Cl– concentration than (B) (C) (D) (E)

does plasma It is stimulated by the presence of HCO3– in the duodenum Pancreatic HCO3– secretion is increased by gastrin Pancreatic enzyme secretion is increased by cholecystokinin (CCK) It is hypotonic

system (CNS) behind and in front of the food bolus behind the food bolus and relaxation of smooth muscle in front of the bolus (E) involves relaxation of smooth muscle simultaneously throughout the small intestine

19. A patient with a duodenal ulcer is treated successfully with the drug cimetidine. The basis for cimetidine’s inhibition of gastric H+ secretion is that it

(A) blocks muscarinic receptors on parietal cells

(B) blocks H2 receptors on parietal cells (C) increases intracellular cyclic adenosine monophosphate (cAMP) levels

(D) blocks H+,K+-adenosine triphosphatase (ATPase)

(E) enhances the action of acetylcholine (ACh) on parietal cells

20. Which of the following substances inhibits gastric emptying?

(A) Secretin (B) Gastrin (C) Cholecystokinin (CCK)

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(D) Vasoactive intestinal peptide (VIP) (E) Gastric inhibitory peptide (GIP)

(A) Decreased serum gastrin levels (B) Increased serum insulin levels (C) Increased absorption of dietary

21. When parietal cells are stimulated, they secrete

(A) (B) (C) (D) (E)

HCl and intrinsic factor HCl and pepsinogen HCl and HCO3– HCO3– and intrinsic factor mucus and pepsinogen

22. A patient with Zollinger–Ellison syndrome would be expected to have which of the following changes?

lipids

(D) Decreased parietal cell mass (E) Peptic ulcer disease 23. Which of the following is the site of Na+–bile acid cotransport?

(A) (B) (C) (D) (E)

Gastric antrum Gastric fundus Duodenum Ileum Colon

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Answers and Explanations 1. The answer is D [II C 1]. Vasoactive intestinal peptide (VIP) is a gastrointestinal (GI) neurocrine that causes relaxation of GI smooth muscle. For example, VIP mediates the relaxation response of the lower esophageal sphincter when a bolus of food approaches it, allowing passage of the bolus into the stomach.

2. The answer is B [IV B 1; Table 6-3; Figure 6-7]. Intrinsic factor is secreted by the parietal cells of the gastric fundus (as is HCl). It is absorbed, with vitamin B12, in the ileum.

3. The answer is B [V D 4 c]. Cholera toxin activates adenylate cyclase and increases cyclic adenosine monophosphate (cAMP) in the intestinal crypt cells. In the crypt cells, cAMP activates the Cl–-secretory channels and produces a primary secretion of Cl–, with Na+ and H2O following.

4. The answer is D [II A 2]. The two hormones have five identical amino acids at the C terminus. Biologic activity of cholecystokinin (CCK) is associated with the seven C-terminal amino acids, and biologic activity of gastrin is associated with the four C-terminal amino acids. Because this CCK heptapeptide contains the five common amino acids, it is logical that CCK should have some gastrin-like properties. G cells secrete gastrin. I cells secrete CCK. The secretin family includes glucagon.

5. The answer is D [V A–C; Table 6-4]. Fructose is the only monosaccharide that is not

absorbed by Na+-dependent cotransport; it is transported by facilitated diffusion. Amino acids are absorbed by Na+-dependent cotransport, but oligopeptides (larger peptide units) are not. Triglycerides are not absorbed without further digestion. The products of lipid digestion, such as fatty acids, are absorbed by simple diffusion.

6. The answer is C [IV D 4]. Ileal resection removes the portion of the small intestine that normally transports bile acids from the lumen of the gut and recirculates them to the liver. Because this process maintains the bile acid pool, new synthesis of bile acids is needed only to replace those bile acids that are lost in the feces. With ileal resection, most of the bile acids secreted are excreted in the feces, and the liver pool is significantly diminished. Bile acids are needed for micelle formation in the intestinal lumen to solubilize the products of lipid digestion so that they can be absorbed. Chylomicrons are formed within the intestinal epithelial cells and are transported to lymph vessels.

7. The answer is A [II A 2 a; Table 6-1]. Cholecystokinin (CCK) inhibits gastric emptying and therefore helps to slow the delivery of food from the stomach to the intestine during periods of high digestive activity. CCK stimulates both functions of the exocrine pancreas— HCO3– secretion and digestive enzyme secretion. It also stimulates the delivery of bile from the gallbladder to the small intestinal lumen by causing contraction of the gallbladder while relaxing the sphincter of Oddi.

8. The answer is C [III C 1]. “Receptive relaxation” of the orad region of the stomach is initiated when food enters the stomach from the esophagus. This parasympathetic (vagovagal) reflex is abolished by vagotomy.

9. The answer is B [II A 1; Table 6-1]. Gastrin’s principal physiologic action is to increase H+ secretion. H+ secretion decreases the pH of the stomach contents. The decreased pH, in turn, inhibits further secretion of gastrin—a classic example of negative feedback.

10. The answer is A [II A 1 b; Table 6-3; Figure 6-7]. Gastrin is secreted by the G cells of the gastric antrum. HCl and intrinsic factor are secreted by the fundus.

219

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11. The answer is F [V E 1; Table 6-4]. Micelles provide a mechanism for solubilizing fatsoluble nutrients in the aqueous solution of the intestinal lumen until the nutrients can be brought into contact with and absorbed by the intestinal epithelial cells. Because vitamin D is fat soluble, it is absorbed in the same way as other dietary lipids. Glycerol is one product of lipid digestion that is water soluble and is not included in micelles. Galactose and leucine are absorbed by Na+-dependent cotransport. Although bile acids are a key ingredient of micelles, they are absorbed by a specific Na+-dependent cotransporter in the ileum. Vitamin B12 is water soluble; thus, its absorption does not require micelles.

12. The answer is A [III E 3]. Both the internal and external anal sphincters must be relaxed to allow feces to be expelled from the body. Rectal smooth muscle contracts and intraabdominal pressure is elevated by expiring against a closed glottis (Valsalva maneuver). Segmentation contractions are prominent in the small intestine during digestion and absorption.

13. The answer is A [IV A 2 a; Table 6-2]. Saliva is characterized by hypotonicity and a high HCO3– concentration (relative to plasma) and by the presence of α-amylase and lingual lipase (not proteases). The high HCO3– concentration is achieved by secretion of HCO3– into saliva by the ductal cells (not reabsorption of HCO3–). Because control of saliva production is parasympathetic, it is abolished by vagotomy.

14. The answer is E [II A 4; Table 6-1]. Glucose-dependent insulinotropic peptide (GIP) is the only gastrointestinal (GI) hormone that is released in response to all three categories of nutrients—fat, protein, and carbohydrate. Oral glucose releases GIP, which, in turn, causes the release of insulin from the endocrine pancreas. This action of GIP explains why oral glucose is more effective than intravenous glucose in releasing insulin.

15. The answer is D [II A 2, 3; Table 6-2]. The major anion in pancreatic secretions is HCO3–

(which is found in higher concentration than in plasma), and the Cl– concentration is lower than in plasma. Pancreatic secretion is stimulated by the presence of fatty acids in the duodenum. Secretin (not gastrin) stimulates pancreatic HCO3– secretion, and cholecystokinin (CCK) stimulates pancreatic enzyme secretion. Pancreatic secretions are always isotonic, regardless of flow rate.

16. The answer is B [V A, B; Table 6-4]. Only monosaccharides can be absorbed by intestinal epithelial cells. Disaccharides, such as sucrose, must be digested to monosaccharides before they are absorbed. On the other hand, proteins are hydrolyzed to amino acids, dipeptides, or tripeptides, and all three forms are transported into intestinal cells for absorption.

17. The answer is D [III A; Figure 6-3]. Slow waves are oscillating resting membrane potentials of the gastrointestinal (GI) smooth muscle. The slow waves bring the membrane potential toward or to threshold, but are not themselves action potentials. If the membrane potential is brought to threshold by a slow wave, then action potentials occur, followed by contraction.

18. The answer is D [III D 2]. Peristalsis is contractile activity that is coordinated by the enteric nervous system [not the central nervous system (CNS)] and propels the intestinal contents forward. Normally, it takes place after sufficient mixing, digestion, and absorption have occurred. To propel the food bolus forward, the smooth muscle must simultaneously contract behind it and relax in front of it.

19. The answer is B [IV B 3 c, d (1), 6]. Cimetidine is a reversible inhibitor of H2 receptors on

parietal cells and blocks H+ secretion. Cyclic adenosine monophosphate (cAMP) [the second messenger for histamine] levels would be expected to decrease, not increase. Cimetidine also blocks the action of acetylcholine (ACh) to stimulate H+ secretion. Omeprazole blocks H+,K+-adenosine triphosphatase (ATPase) directly.

20. The answer is C [II A 2 a; Table 6-1]. Cholecystokinin (CCK) is the most important hormone for digestion and absorption of dietary fat. In addition to causing contraction of the

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gallbladder, it inhibits gastric emptying. As a result, chyme moves more slowly from the stomach to the small intestine, thus allowing more time for fat digestion and absorption.

21. The answer is A [IV B 1; Table 6-3]. The gastric parietal cells secrete HCl and intrinsic factor. The chief cells secrete pepsinogen.

22. The answer is E [II A 1 d; V C 3 b]. Zollinger–Ellison syndrome (gastrinoma) is a tumor of the non–β-cell pancreas. The tumor secretes gastrin, which then circulates to the gastric parietal cells to produce increased H+ secretion, peptic ulcer, and parietal cell growth (trophic effect of gastrin). Because the tumor does not involve the pancreatic β cells, insulin levels should be unaffected. Absorption of lipids is decreased (not increased) because increased H+ secretion decreases the pH of the intestinal lumen and inactivates pancreatic lipases.

23. The answer is D [IV D 4]. Bile salts are recirculated to the liver in the enterohepatic circulation via a Na+–bile acid cotransporter located in the ileum of the small intestine.

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chapter

7

Endocrine Physiology

I. OVERVIEW OF HORMONES A. See Table 7-1 for a list of hormones, including abbreviations, glands of origin, and major actions. B. Hormone synthesis 1. Protein and peptide hormone synthesis ■ ■ ■

Preprohormone synthesis occurs in the endoplasmic reticulum and is directed by a specific mRNA. Signal peptides are cleaved from the preprohormone, producing a prohormone, which is transported to the Golgi apparatus. Additional peptide sequences are cleaved in the Golgi apparatus to form the hormone, which is packaged in secretory granules for later release.

2. Steroid hormone synthesis ■

Steroid hormones are derivatives of cholesterol (the biosynthetic pathways are described in V A 1).

3. Amine hormone synthesis ■

Amine hormones (thyroid hormones, epinephrine, norepinephrine) are derivatives of tyrosine (the biosynthetic pathway for thyroid hormones is described in IV A).

C. Regulation of hormone secretion 1. Negative feedback ■ ■ ■ ■

is the most commonly applied principle for regulating hormone secretion. is self-limiting. A hormone has biologic actions that, directly or indirectly, inhibit further secretion of the hormone. For example, insulin is secreted by the pancreatic beta cells in response to an increase in blood glucose. In turn, insulin causes an increase in glucose uptake into cells that results in decreased blood glucose concentration. The decrease in blood glucose concentration then decreases further secretion of insulin.

2. Positive feedback ■ ■ ■ ■

222

is rare. is explosive and self-reinforcing. A hormone has biologic actions that, directly or indirectly, cause more secretion of the hormone. For example, the surge of luteinizing hormone (LH) that occurs just before ovulation is a result of positive feedback of estrogen on the anterior pituitary. LH then acts on the ovaries and causes more secretion of estrogen.

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Chapter 7 Endocrine Physiology t a b l e

7-1

223

Master List of Hormones

Hormone

Abbreviation

Gland of Origin

Major Actions*

Thyrotropin-releasing hormone Corticotropin-releasing hormone Gonadotropin-releasing hormone Growth hormone–releasing hormone Somatotropin release-inhibiting hormone (somatostatin) Prolactin-inhibiting factor (dopamine) Thyroid-stimulating hormone

TRH CRH GnRH GHRH SRIF

Hypothalamus Hypothalamus Hypothalamus Hypothalamus Hypothalamus

Stimulates secretion of TSH and prolactin Stimulates secretion of ACTH Stimulates secretion of LH and FSH Stimulates secretion of growth hormone Inhibits secretion of growth hormone

PIF TSH

Hypothalamus Anterior pituitary

Follicle-stimulating hormone

FSH

Anterior pituitary

Luteinizing hormone

LH

Anterior pituitary

Growth hormone

GH

Anterior pituitary

Inhibits secretion of prolactin Stimulates synthesis and secretion of thyroid hormones Stimulates growth of ovarian follicles and estrogen secretion Promotes sperm maturation (testes) Stimulates ovulation, formation of corpus luteum, and synthesis of estrogen and progesterone (ovary) Stimulates synthesis and secretion of testosterone (testes) Stimulates protein synthesis and overall growth Stimulates milk production and breast development Stimulates synthesis and secretion of adrenal cortical hormones ? in human Stimulates melanin synthesis (? humans) Milk ejection; uterine contraction Stimulates H2O reabsorption by renal collecting ducts Skeletal growth; ↑ O2 consumption; heat production; ↑ protein, fat, and carbohydrate use; maturation of nervous system (perinatal) Stimulates gluconeogenesis; anti-inflammatory; immunosuppression Growth and development of female reproductive organs; follicular phase of menstrual cycle Luteal phase of menstrual cycle Spermatogenesis; male secondary sex characteristics ↑ Serum [Ca2+]; ↓ serum [phosphate] ↓ Serum [Ca2+]

Prolactin Adrenocorticotropic hormone

Anterior pituitary ACTH

β-Lipotropin Melanocyte-stimulating hormone Oxytocin Antidiuretic hormone (vasopressin)

ADH

L-thyroxine Triiodothyronine

T4 T3

MSH

Anterior pituitary Anterior pituitary Anterior pituitary Posterior pituitary Posterior pituitary Thyroid gland

Glucocorticoids (cortisol)

Adrenal cortex

Estradiol

Ovary

Progesterone Testosterone

Ovary Testes

Parathyroid hormone Calcitonin

PTH

Aldosterone

Parathyroid gland Thyroid gland (parafollicular cells) Adrenal cortex

1,25-Dihydroxycholecalciferol

Kidney (activation)

Insulin

Human chorionic gonadotropin

HCG

Pancreas (beta cells) Pancreas (alpha cells) Placenta

Human placental lactogen

HPL

Placenta

Glucagon

*See text for more complete description of each hormone.

↑ Renal Na+ reabsorption; ↑ renal K+ secretion; ↑ renal H+ secretion ↑ Intestinal Ca2+ absorption; ↑ bone mineralization ↓ Blood [glucose]; ↓ blood [amino acid]; ↓ blood [fatty acid] ↑ Blood [glucose]; ↑ blood [fatty acid] ↑ Estrogen and progesterone synthesis in corpus luteum of pregnancy Same actions as growth hormone and prolactin during pregnancy

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D. Regulation of receptors ■

Hormones determine the sensitivity of the target tissue by regulating the number or sensitivity of receptors.

1. Down-regulation of receptors ■ ■

A hormone decreases the number or affinity of receptors for itself or for another hormone. For example, in the uterus, progesterone down-regulates its own receptor and the receptor for estrogen.

2. Up-regulation of receptors ■ ■

A hormone increases the number or affinity of receptors for itself or for another hormone. For example, in the ovary, estrogen up-regulates its own receptor and the receptor for LH.

II. CELL MECHANISMS AND SECOND MESSENGERS (TABLE 7-2) A. G proteins ■

■ ■ ■ ■

■

are guanosine triphosphate (GTP)-binding proteins that couple hormone receptors to adjacent effector molecules. For example, in the cyclic adenosine monophosphate (cAMP) second messenger system, G proteins couple the hormone receptor to adenylate cyclase. are used in the adenylate cyclase, Ca2+–calmodulin, and inositol 1,4,5-triphosphate (IP3) second messenger systems. have intrinsic GTPase activity. have three subunits: α, β, and γ. The ` subunit can bind either guanosine diphosphate (GDP) or GTP. When GDP is bound to the α subunit, the G protein is inactive. When GTP is bound, the G protein is active. G proteins can be either stimulatory (Gs) or inhibitory (Gi). Stimulatory or inhibitory activity resides in the α subunits, which are accordingly called αs and αi.

B. Adenylate cyclase mechanism (Figure 7-1) 1. Hormone binds to a receptor in the cell membrane (step 1). 2. GDP is released from the G protein and replaced by GTP (step 2), which activates the G protein. The G protein then activates or inhibits adenylate cyclase. If the G protein is stimulatory (Gs), then adenylate cyclase will be activated. If the G protein is inhibitory (Gi), t a b l e

7-2

Mechanisms of Hormone Action

cAMP Mechanism

IP3 Mechanism

Steroid Hormone Mechanism

Other Mechanisms

ACTH LH and FSH TSH ADH (V2 receptor) HCG MSH CRH β1 and β2 Receptors Calcitonin PTH Glucagon

GnRH TRH GHRH Angiotensin II ADH (V1 receptor) Oxytocin α1 Receptors

Glucocorticoids Estrogen Testosterone Progesterone Aldosterone Vitamin D Thyroid hormone

Activation of tyrosine kinase Insulin IGF-1 cGMP ANP EDRF Nitric oxide

ANP = atrial natriuretic peptide; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; EDRF = endothelium-derived relaxing factor; IGF = insulin-like growth factor; IP3 = inositol 1,4,5-triphosphate. See Table 7-1 for other abbreviations.

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Chapter 7 Endocrine Physiology

225

Hormone 1 Receptor

~

~

G protein (stimulatory or inhibitory) 2

GDP

adenylate cyclase 3

GTP e

as

ie

r ste

d ho

cAMP

ATP

4

p

os

ph

5'-AMP (inactive)

Activates protein kinase A 5 Phosphorylates proteins 6

Physiologic actions FIGURE 7-1 Mechanism of hormone action—adenylate cyclase. ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; GDP = guanosine diphosphate; GTP = guanosine triphosphate.

then adenylate cyclase will be inhibited (not shown). Intrinsic GTPase activity in the G protein converts GTP back to GDP (not shown). 3. Activated adenylate cyclase then catalyzes the conversion of adenosine triphosphate (ATP) to cAMP (step 3). 4. cAMP activates protein kinase A (step 4), which phosphorylates specific proteins (step 5), producing highly specific physiologic actions (step 6). 5. cAMP is degraded to 5’-AMP by phosphodiesterase, which is inhibited by caffeine. Therefore, phosphodiesterase inhibitors would be expected to augment the physiologic actions of cAMP.

C. IP3 mechanism (Figure 7-2) 1. Hormone binds to a receptor in the cell membrane (step 1) and, via a G protein (step 2), activates phospholipase C (step 3). 2. Phospholipase C liberates diacylglycerol and IP3 from membrane lipids (step 4). 3. IP3 mobilizes Ca2+ from the endoplasmic reticulum (step 5). Together, Ca2+ and diacylglycerol activate protein kinase C (step 6), which phosphorylates proteins and causes specific physiologic actions (step 7). D. Ca2+–calmodulin mechanism (Figure 7-3) 1. Hormone binds to a receptor in the cell membrane (step 1) and, via a G protein, has two actions: it opens cell membrane Ca2+ channels and it releases Ca2+ from the endoplasmic reticulum (step 2). Together, these two actions produce an increase in intracellular [Ca2+] (step 3). 2. Ca2+ binds to calmodulin (step 4), and the Ca2+–calmodulin complex produces physiologic actions (step 5).

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226


Hormone 1

~

Receptor

G protein GDP

2

~

phospholipase C 3

GTP

Phospholipids 4 Diacylglycerol 6

Arachidonic acid

IP3 5

Protein kinase C Prostaglandins

4

Ca2+ released from endoplasmic reticulum

7

Physiologic actions FIGURE 7-2 Mechanism of hormone action—inositol 1,4,5-triphosphate (IP3)–Ca2+. GDP = guanosine diphosphate; GTP = guanosine triphosphate.

Hormone 1 Receptor

~

2

G protein 2

Mobilizes Ca2+ from intracellular stores

Opens Ca2+ channels in cell membrane

3 [Ca2+] 4 Ca2+ – calmodulin 5

Physiologic actions

FIGURE 7-3 Mechanism of hormone action—Ca2+-calmodulin.

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Steroid hormone Cell membrane 1 Hormone binds to receptor 2 Hormone-receptor complex enters nucleus and dimerizes 3 Hormone-receptor dimers bind SREs of DNA 4

DNA transcription

mRNAs 5

Translation

New proteins 6

FIGURE 7-4 Mechanism of hormone action—steroid hormones. SREs = steroid-responsive elements.

Physiologic actions

E. Steroid hormone and thyroid hormone mechanism (Figure 7-4) 1. Steroid (or thyroid) hormone diffuses across the cell membrane and binds to its receptor (step 1).

2. The hormone-receptor complex enters the nucleus and dimerizes (step 2). 3. The hormone-receptor dimers are transcription factors that bind to steroid-responsive elements (SREs) of DNA (step 3) and initiate DNA transcription (step 4). 4. New messenger RNA is produced, leaves the nucleus, and is translated to synthesize new proteins (step 5).

5. The new proteins that are synthesized have specific physiologic actions. For example, 1,25-dihydroxycholecalciferol induces the synthesis of calbindin D-28K, a Ca2+-binding protein in the intestine; aldosterone induces the synthesis of Na+ channels in the renal principal cells.

III. PITUITARY GLAND (HYPOPHYSIS) A. Hypothalamic–pituitary relationships 1. The anterior lobe of the pituitary gland is linked to the hypothalamus by the hypothalamic–hypophysial portal system. Thus, blood from the hypothalamus that contains high concentrations of hypothalamic hormones is delivered directly to the anterior pituitary. Hypothalamic hormones [e.g., growth hormone–releasing hormone

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Board Review Series: Physiology (GHRH)] then stimulate or inhibit the release of anterior pituitary hormones (e.g., growth hormone). 2. The posterior lobe of the pituitary gland is derived from neural tissue. The nerve cell bodies are located in hypothalamic nuclei. Posterior pituitary hormones are synthesized in the nerve cell bodies, packaged in secretory granules, and transported down the axons to the posterior pituitary for release into the circulation.

B. Hormones of the anterior lobe of the pituitary ■ ■

are growth hormone, prolactin, thyroid-stimulating hormone (TSH), LH, follicle-stimulating hormone (FSH), and adrenocorticotropic hormone (ACTH). Growth hormone and prolactin are discussed in detail in this section. TSH, LH, FSH, and ACTH are discussed in context (e.g., TSH with thyroid hormone) in later sections of this chapter.

1. TSH, LH, and FSH ■

belong to the same glycoprotein family. Each has an α subunit and a β subunit. The ` subunits are identical. The β subunits are different and are responsible for the unique biologic activity of each hormone.

2. ACTH, melanocyte-stimulating hormone (MSH), a-lipotropin, and a-endorphin (Figure 7-5) ■ ■

are derived from a single precursor, pro-opiomelanocortin (POMC). `-MSH and a-MSH are produced in the intermediary lobe, which is rudimentary in adult humans.

3. Growth hormone (somatotropin) ■ ■

is the most important hormone for normal growth to adult size. is a single-chain polypeptide that is homologous with prolactin and human placental lactogen.

a. Regulation of growth hormone secretion (Figure 7-6) ■ ■ ■

Growth hormone is released in pulsatile fashion. Secretion is increased by sleep, stress, hormones related to puberty, starvation, exercise, and hypoglycemia. Secretion is decreased by somatostatin, somatomedins, obesity, hyperglycemia, and pregnancy.

POMC

β-Lipotropin

ACTH intermediate

+

Fragment

ACTH

+

β-Endorphin

γ-Lipotropin

+

FIGURE 7-5 Pro-opiomelanocortin is the precursor for adrenocorticotropic hormone (ACTH), β-lipotropin, and β-endorphin in the anterior pituitary.

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229

– Hypothalamus +

Somatostatin (SRIF)

GHRH

–

+ –

+

Anterior pituitary

Growth hormone

Somatomedins (IGF)

Target tissues

Somatomedins (IGF)

FIGURE 7-6 Control of growth hormone secretion. GHRH = growth hormone–releasing hormone; IGF = insulin-like growth factor; SRIF = somatotropin release-inhibiting factor.

(1) Hypothalamic control—GHRH and somatostatin ■ ■

GHRH stimulates the synthesis and secretion of growth hormone. Somatostatin inhibits secretion of growth hormone by blocking the response of the anterior pituitary to GHRH.

(2) Negative feedback control by somatomedins ■ ■

Somatomedins are produced when growth hormone acts on target tissues. Somatomedins inhibit the secretion of growth hormone by acting directly on the anterior pituitary and by stimulating the secretion of somatostatin from the hypothalamus.

(3) Negative feedback control by GHRH and growth hormone ■ ■

GHRH inhibits its own secretion from the hypothalamus. Growth hormone also inhibits its own secretion by stimulating the secretion of somatostatin from the hypothalamus.

b. Actions of growth hormone ■ ■

In the liver, growth hormone generates the production of somatomedins [insulin-like growth factors (IGF)], which serve as the intermediaries of several physiologic actions. The IGF receptor has tyrosine kinase activity, similar to the insulin receptor.

(1) Direct actions of growth hormone (a) ↓ glucose uptake into cells (diabetogenic) (b) ↑ lipolysis (c) ↑ protein synthesis in muscle and ↑ lean body mass (d) ↑ production of IGF (2) Actions of growth hormone via IGF (a) ↑ protein synthesis in chondrocytes and ↑ linear growth (pubertal growth spurt) (b) ↑ protein synthesis in muscle and ↑ lean body mass (c) ↑ protein synthesis in most organs and ↑ organ size

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c. Pathophysiology of growth hormone (1) Growth hormone deficiency ■ ■

in children causes failure to grow, short stature, mild obesity, and delayed puberty. can be caused by:

(a) (b) (c) (d)

Lack of anterior pituitary growth hormone Hypothalamic dysfunction (↓ GHRH) Failure to generate IGF in the liver Growth hormone receptor deficiency (2) Growth hormone excess ■ ■

can be treated with somatostatin analogs (e.g., octreotide), which inhibit growth hormone secretion. Hypersecretion of growth hormone causes acromegaly.

(a) Before puberty, excess growth hormone causes increased linear growth (gigantism). (b) After puberty, excess growth hormone causes increased periosteal bone growth, increased organ size, and glucose intolerance.

4. Prolactin ■ ■ ■

is the major hormone responsible for lactogenesis. participates, with estrogen, in breast development. is structurally homologous to growth hormone.

a. Regulation of prolactin secretion (Figure 7-7 and Table 7-3) (1) Hypothalamic control by dopamine- and thyrotropin-releasing hormone (TRH) ■

■

Prolactin secretion is tonically inhibited by dopamine [prolactin-inhibiting factor (PIF)] secreted by the hypothalamus. Thus, interruption of the hypothalamic – pituitary tract causes increased secretion of prolactin and sustained lactation. TRH increases prolactin secretion.

(2) Negative feedback control ■

Prolactin inhibits its own secretion by stimulating the hypothalamic release of dopamine.

Hypothalamus +

Dopamine (PIF)

TRH

–

+

Anterior pituitary

Prolactin

Mammary glands

FIGURE 7-7 Control of prolactin secretion. PIF = prolactin-inhibiting factor; TRH = thyrotropin-releasing hormone.

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7-3

231

Regulation of Prolactin Secretion

Factors that Increase Prolactin Secretion

Factors that Decrease Prolactin Secretion

Estrogen (pregnancy) Breast-feeding Sleep Stress TRH Dopamine antagonists

Dopamine Bromocriptine (dopamine agonist) Somatostatin Prolactin (by negative feedback)

TRH = thyrotropin-releasing hormone.

b. Actions of prolactin (1) Stimulates milk production in the breast (casein, lactalbumin) (2) Stimulates breast development (in a supportive role with estrogen) (3) Inhibits ovulation by decreasing synthesis and release of gonadotropin-releasing hormone (GnRH)

(4) Inhibits spermatogenesis (by decreasing GnRH) c. Pathophysiology of prolactin (1) Prolactin deficiency (destruction of the anterior pituitary) ■

results in the failure to lactate.

(2) Prolactin excess ■ results from hypothalamic destruction (due to loss of the tonic “inhibitory” control by dopamine), or from prolactin-secreting tumors (prolactinomas). ■ causes galactorrhea and decreased libido. ■ causes failure to ovulate and amenorrhea because it inhibits GnRH secretion. ■ can be treated with bromocriptine, which reduces prolactin secretion by acting as a dopamine agonist. C. Hormones of the posterior lobe of the pituitary ■ ■ ■ ■

are antidiuretic hormone (ADH) and oxytocin. are homologous nonapeptides. are synthesized in hypothalamic nuclei and are packaged in secretory granules with their respective neurophysins. travel down the nerve axons for secretion by the posterior pituitary.

1. ADH (see Chapter 5 VII) ■ ■

originates primarily in the supraoptic nuclei of the hypothalamus. regulates serum osmolarity by increasing the H2O permeability of the late distal tubules and collecting ducts.

a. Regulation of ADH secretion (Table 7-4)

t a b l e

7-4

Regulation of ADH Secretion

Factors that Increase ADH Secretion

Factors that Decrease ADH Secretion

Serum osmolarity Volume contraction Pain Nausea (powerful stimulant) Hypoglycemia Nicotine, opiates, antineoplastic drugs

↓ Serum osmolarity Ethanol α-Agonists ANP

ADH = antidiuretic hormone; ANP = atrial natriuretic peptide.

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b. Actions of ADH (1) ↑ H2O permeability (aquaporin 2, AQP2) of the principal cells of the late distal tubule and collecting duct (via a V2 receptor and an adenylate cyclase–cAMP mechanism) (2) Constriction of vascular smooth muscle (via a V1 receptor and an IP3/Ca2+ mechanism)

c. Pathophysiology of ADH (see Chapter 5 VII) 2. Oxytocin ■ ■

originates primarily in the paraventricular nuclei of the hypothalamus. causes ejection of milk from the breast when stimulated by suckling.

a. Regulation of oxytocin secretion (1) Suckling ■ ■ ■

is the major stimulus for oxytocin secretion. Afferent fibers carry impulses from the nipple to the spinal cord. Relays in the hypothalamus trigger the release of oxytocin from the posterior pituitary. The sight or sound of the infant may stimulate the hypothalamic neurons to secrete oxytocin, even in the absence of suckling.

(2) Dilation of the cervix and orgasm ■

increases the secretion of oxytocin.

b. Actions of oxytocin (1) Contraction of myoepithelial cells in the breast ■

Milk is forced from the mammary alveoli into the ducts and delivered to the infant.

(2) Contraction of the uterus ■

■

During pregnancy, oxytocin receptors in the uterus are up-regulated as parturition approaches, although the role of oxytocin in normal labor is uncertain. Oxytocin can be used to induce labor and reduce postpartum bleeding.

IV. THYROID GLAND A. Synthesis of thyroid hormones (Figure 7-8) ■

Each step in synthesis is stimulated by TSH.

1. Thyroglobulin is synthesized from tyrosine in the thyroid follicular cells, packaged in secretory vesicles, and extruded into the follicular lumen (step 1).

2. The iodide (I–) pump, or Na+–I– cotransport ■ ■ ■

is present in the thyroid follicular epithelial cells. actively transports I– into the thyroid follicular cells for subsequent incorporation into thyroid hormones (step 2). is inhibited by thiocyanate and perchlorate anions.

3. Oxidation of I– to I2 ■ ■ ■ ■

is catalyzed by a peroxidase enzyme in the follicular cell membrane (step 3). I2 is the reactive form, which will be “organified” by combination with tyrosine on thyroglobulin. The peroxidase enzyme is inhibited by propylthiouracil, which is used therapeutically to reduce thyroid hormone synthesis for the treatment of hyperthyroidism. The same peroxidase enzyme catalyzes the remaining organification and coupling reactions involved in the synthesis of thyroid hormones.

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Chapter 7 Endocrine Physiology Blood

Thyroid follicular epithelial cell

Follicular lumen

1

TG

ine ros Ty

TG

Thyroglobulin

2

I–

+ I–

3

I2

peroxidase

4

Na+

8

233

Organification of I 2 peroxidase

deiodinase

TG

MIT DIT

MIT, DIT 5

T4 , T3 (to circulation)

7

TG

T4 T3 MIT DIT

Coupling reaction peroxidase

6 TG Endocytosis

T4 T3 MIT DIT

FIGURE 7-8 Steps in the synthesis of thyroid hormones. Each step is stimulated by thyroid-stimulating hormone. DIT = diiodotyrosine; I– = iodide; MIT = monoiodotyrosine; T3 = triiodothyronine; T4 = thyroxine; TG = thyroglobulin.

4. Organification of I2 ■ ■

At the junction of the follicular cells and the follicular lumen, tyrosine residues of thyroglobulin react with I2 to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) (step 4). High levels of I– inhibit organification and, therefore, inhibit synthesis of thyroid hormone (Wolff–Chaikoff effect).

5. Coupling of MIT and DIT ■

While MIT and DIT are attached to thyroglobulin, two coupling reactions occur (step 5).

a. When two molecules of DIT combine, thyroxine (T4) is formed. b. When one molecule of DIT combines with one molecule of MIT, triiodothyronine (T3) is formed. ■

More T4 than T3 is synthesized, although T3 is more active.

c. Iodinated thyroglobulin is stored in the follicular lumen until the thyroid gland is stimulated to secrete thyroid hormones.

6. Stimulation of thyroid cells by TSH ■

■

When the thyroid cells are stimulated, iodinated thyroglobulin is taken back into the follicular cells by endocytosis (step 6). Lysosomal enzymes then digest thyroglobulin, releasing T4 and T3 into the circulation (step 7). Leftover MIT and DIT are deiodinated by thyroid deiodinase (step 8). The I2 that is released is reutilized to synthesize more thyroid hormones. Therefore, deficiency of thyroid deiodinase mimics I2 deficiency.

7. Binding of T3 and T4 ■

In the circulation, most of the T3 and T4 is bound to thyroxine-binding globulin (TBG).

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Hypothalamus

TRH + –

Anterior pituitary

TSH + Thyroid

T3, T4

FIGURE 7-9 Control of thyroid hormone secretion. T3 = triiodothyronine; T4 = thyroxine; TRH = thyrotropin-releasing hormone; TSH = thyroidstimulating hormone.

a. In hepatic failure, TBG levels decrease, leading to a decrease in total thyroid hormone levels, but normal levels of free hormone.

b. In pregnancy, TBG levels increase, leading to an increase in total thyroid hormone levels, but normal levels of free hormone (i.e., clinically, euthyroid).

8. Conversion of T4 to T3 and reverse T3 (rT3) ■ ■ ■

In the peripheral tissues, T4 is converted to T3 by 5’-iodinase (or to rT3). T3 is more biologically active than T4. rT3 is inactive.

B. Regulation of thyroid hormone secretion (Figure 7-9) 1. Hypothalamic–pituitary control—TRH and TSH a. TRH is secreted by the hypothalamus and stimulates the secretion of TSH by the anterior pituitary.

b. TSH increases both the synthesis and the secretion of thyroid hormones by the follicular cells via an adenylate cyclase–cAMP mechanism. ■

Chronic elevation of TSH causes hypertrophy of the thyroid gland.

c. T3 down-regulates TRH receptors in the anterior pituitary and thereby inhibits TSH secretion.

2. Thyroid-stimulating immunoglobulins ■ ■ ■

are components of the immunoglobulin G (IgG) fraction of plasma proteins and are antibodies to TSH receptors on the thyroid gland. bind to TSH receptors and, like TSH, stimulate the thyroid gland to secrete T3 and T4. circulate in high concentrations in patients with Graves’ disease, which is characterized by high circulating levels of thyroid hormones and, accordingly, low concentrations of TSH (caused by feedback inhibition of thyroid hormones on the anterior pituitary).

C. Actions of thyroid hormone ■

T3 is three to four times more potent than T4. The target tissues convert T4 to T3 (see IV A 8).

1. Growth ■

Attainment of adult stature requires thyroid hormone.

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Chapter 7 Endocrine Physiology ■ ■

235

Thyroid hormones act synergistically with growth hormone and somatomedins to promote bone formation. Thyroid hormones stimulate bone maturation as a result of ossification and fusion of the growth plates. In thyroid hormone deficiency, bone age is less than chronologic age.

2. Central nervous system (CNS) a. Perinatal period ■ ■

Maturation of the CNS requires thyroid hormone in the perinatal period. Thyroid hormone deficiency causes irreversible mental retardation. Because there is only a brief perinatal period when thyroid hormone replacement therapy is helpful, screening for neonatal hypothyroidism is mandatory.

b. Adulthood ■ ■

Hyperthyroidism causes hyperexcitability and irritability. Hypothyroidism causes listlessness, slowed speech, somnolence, impaired memory, and decreased mental capacity.

3. Autonomic nervous system ■

Thyroid hormone has many of the same actions as the sympathetic nervous system because it up-regulates a1-adrenergic receptors in the heart. Therefore, a useful adjunct therapy for hyperthyroidism is treatment with a β-adrenergic blocking agent, such as propranolol.

4. Basal metabolic rate (BMR) ■

■

O2 consumption and BMR are increased by thyroid hormone in all tissues except the brain, gonads, and spleen. The resulting increase in heat production underlies the role of thyroid hormone in temperature regulation. Thyroid hormone increases the synthesis of Na+,K+-ATPase and consequently increases O2 consumption related to Na+–K+ pump activity.

5. Cardiovascular and respiratory systems ■

Effects of thyroid hormone on cardiac output and ventilation rate combine to ensure that more O2 is delivered to the tissues.

a. Heart rate and stroke volume are increased. These effects combine to produce increased cardiac output. b. Ventilation rate is increased. 6. Metabolic effects ■

Overall, metabolism is increased to meet the demand for substrate associated with the increased rate of O2 consumption.

a. Glucose absorption from the gastrointestinal tract is increased. b. Glycogenolysis, gluconeogenesis, and glucose oxidation (driven by demand for ATP) are increased.

c. Lipolysis is increased. d. Protein synthesis and degradation are increased. The overall effect of thyroid hormone is catabolic. D. Pathophysiology of the thyroid gland (Table 7-5)

V. ADRENAL CORTEX AND ADRENAL MEDULLA (FIGURE 7-10) A. Adrenal cortex 1. Synthesis of adrenocortical hormones (Figure 7-11) ■ ■

The zona glomerulosa produces aldosterone. The zona fasciculata produces mostly glucocorticoids (cortisol).

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7-5

t a b l e

Pathophysiology of the Thyroid Gland

Hyperthyroidism

Hypothyroidism

Symptoms

↑ metabolic rate Weight loss Negative nitrogen balance ↑ heat production (sweating) ↑ cardiac output Dyspnea Tremor, weakness Exophthalmos Goiter

Causes

Graves’ disease (antibodies to TSH receptor)

↓ metabolic rate Weight gain Positive nitrogen balance ↓ heat production (cold sensitivity) ↓ cardiac output Hypoventilation Lethargy, mental slowness Drooping eyelids Myxedema Growth and mental retardation (perinatal) Goiter Thyroiditis (autoimmune thyroiditis; Hashimoto’s thyroiditis) Surgical removal of thyroid I– deficiency Cretinism (congenital) ↓ TRH or TSH ↑ (because of decreased feedback inhibition on anterior pituitary by low thyroid hormone levels) ↓ (if primary defect is in hypothalamus or anterior pituitary) Thyroid hormone replacement

Thyroid neoplasm

TSH levels

↓ (because of feedback inhibition on anterior pituitary by high thyroid hormone levels)

Treatment

Propylthiouracil (inhibits thyroid hormone synthesis by blocking peroxidase) Thyroidectomy 131I (destroys thyroid) β-blockers (adjunct therapy)

See Table 7-1 for abbreviations. ■

The zona reticularis produces mostly androgens (dehydroepiandrosterone and androstenedione).

a. 21-carbon steroids ■ ■

include progesterone, deoxycorticosterone, aldosterone, and cortisol. Progesterone is the precursor for the others in the 21-carbon series.

Aldosterone

Glucocorticoids

Androgens

Catecholamines

Adrenal medulla FIGURE 7-10 Secretory products of the adrenal cortex and medulla.

Adrenal cortex

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237

ACTH +

Cholesterol

cholesterol desmolase 17α-hydroxylase

Pregnenolone

17,20-lyase

3β-hydroxysteroid dehydrogenase

3β-hydroxysteroid dehydrogenase

Progesterone

Dehydroepiandrosterone

17-Hydroxypregnenolone

17α-hydroxylase

21β-hydroxylase

3β-hydroxysteroid dehydrogenase 17,20-lyase

17-Hydroxyprogesterone

Androstenedione

21β-hydroxylase

11-Deoxycorticosterone

11β-hydroxylase

11-Deoxycortisol

Testosterone

11β-hydroxylase

Corticosterone

Cortisol

Estradiol

aldosterone synthase

Aldosterone

+ Angiotensin II

Product of zona glomerulosa

Product of zona fasciculata

Products of zona reticularis

FIGURE 7-11 Synthetic pathways for glucocorticoids, androgens, and mineralocorticoids in the adrenal cortex. ACTH = adrenocorticotropic hormone.

■ ■

Hydroxylation at C-21 leads to the production of deoxycorticosterone, which has mineralocorticoid (but not glucocorticoid) activity. Hydroxylation at C-17 leads to the production of glucocorticoids (cortisol).

b. 19-carbon steroids ■ ■

■ ■

have androgenic activity and are precursors to the estrogens. If the steroid has been previously hydroxylated at C-17, the C20,21 side chain can be cleaved to yield the 19-carbon steroids dehydroepiandrosterone or androstenedione in the adrenal cortex. Adrenal androgens have a ketone group at C-17 and are excreted as 17-ketosteroids in the urine. In the testes, androstenedione is converted to testosterone.

c. 18-carbon steroids ■ ■

have estrogenic activity. Oxidation of the A ring (aromatization) to produce estrogens occurs in the ovaries and placenta, but not in the adrenal cortex or testes.

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Higher centers

–

Hypothalamus

CRH + – Anterior pituitary

ACTH +

Adrenal cortex

Cortisol

FIGURE 7-12 Control of glucocorticoid secretion. ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone.

2. Regulation of secretion of adrenocortical hormones a. Glucocorticoid secretion (Figure 7-12) ■ ■

oscillates with a 24-hour periodicity, or circadian rhythm. For those who sleep at night, cortisol levels are highest just before waking (≈8 A.M.) and lowest in the evening (≈12 midnight).

(1) Hypothalamic control—corticotropin-releasing hormone (CRH) ■ ■ ■ ■

CRH-containing neurons are located in the paraventricular nuclei of the hypothalamus. When these neurons are stimulated, CRH is released into hypothalamic– hypophysial portal blood and delivered to the anterior pituitary. CRH binds to receptors on corticotrophs of the anterior pituitary and directs them to synthesize POMC (the precursor to ACTH) and secrete ACTH. The second messenger for CRH is cAMP.

(2) Anterior lobe of the pituitary—ACTH ■

■ ■ ■

ACTH increases steroid hormone synthesis in all zones of the adrenal cortex by stimulating cholesterol desmolase and increasing the conversion of cholesterol to pregnenolone. ACTH also up-regulates its own receptor so that the sensitivity of the adrenal cortex to ACTH is increased. Chronically increased levels of ACTH cause hypertrophy of the adrenal cortex. The second messenger for ACTH is cAMP.

(3) Negative feedback control—cortisol ■ ■ ■

Cortisol inhibits the secretion of CRH from the hypothalamus and the secretion of ACTH from the anterior pituitary. When cortisol (glucocorticoid) levels are chronically elevated, the secretion of CRH and ACTH is inhibited by negative feedback. The dexamethasone suppression test is based on the ability of dexamethasone (a synthetic glucocorticoid) to inhibit ACTH secretion. In normal persons, lowdose dexamethasone inhibits or “suppresses” ACTH secretion and, consequently, cortisol secretion. In persons with ACTH-secreting tumors, low-dose

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dexamethasone does not inhibit cortisol secretion, but high-dose dexamethasone does. In persons with adrenal cortical tumors, neither low- nor high-dose dexamethasone inhibits cortisol secretion.

b. Aldosterone secretion (see Chapter 3 VI B) ■

is under tonic control by ACTH, but is separately regulated by the renin– angiotensin system and by potassium.

(1) Renin–angiotensin–aldosterone system (a) Decreases in blood volume cause a decrease in renal perfusion pressure, which in turn increases renin secretion. Renin, an enzyme, catalyzes the conversion of angiotensinogen to angiotensin I. Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE). (b) Angiotensin II acts on the zona glomerulosa of the adrenal cortex to increase the conversion of corticosterone to aldosterone. (c) Aldosterone increases renal Na+ reabsorption, thereby restoring extracellular fluid (ECF) volume and blood volume to normal.

(2) Hyperkalemia increases aldosterone secretion. Aldosterone increases renal K+ secretion, restoring blood [K+] to normal.

3. Actions of glucocorticoids (cortisol) ■

Overall, glucocorticoids are essential for the response to stress.

a. Stimulation of gluconeogenesis ■

Glucocorticoids increase gluconeogenesis by the following mechanisms: (1) They increase protein catabolism in muscle and decrease protein synthesis, thereby providing more amino acids to the liver for gluconeogenesis. (2) They decrease glucose utilization and insulin sensitivity of adipose tissue. (3) They increase lipolysis, which provides more glycerol to the liver for gluconeogenesis.

b. Anti-inflammatory effects (1) Glucocorticoids induce the synthesis of lipocortin, an inhibitor of phospholipase A2.

(Phospholipase A2 is the enzyme that liberates arachidonate from membrane phospholipids, providing the precursor for prostaglandin and leukotriene synthesis.) Because prostaglandins and leukotrienes are involved in the inflammatory response, glucocorticoids have anti-inflammatory properties by inhibiting the formation of the precursor (arachidonate). (2) Glucocorticoids inhibit the production of interleukin-2 (IL-2) and inhibit the proliferation of T lymphocytes. (3) Glucocorticoids inhibit the release of histamine and serotonin from mast cells and platelets.

c. Suppression of the immune response ■

Glucocorticoids inhibit the production of IL-2 and T lymphocytes, both of which are critical for cellular immunity. In pharmacologic doses, glucocorticoids are used to prevent rejection of transplanted organs.

d. Maintenance of vascular responsiveness to catecholamines ■

Cortisol up-regulates `1 receptors on arterioles, increasing their sensitivity to the vasoconstrictor effect of norepinephrine. Thus, with cortisol excess, arterial pressure increases; with cortisol deficiency, arterial pressure decreases.

4. Actions of mineralocorticoids (aldosterone) [see Chapters 3 and 5] a. ä renal Na+ reabsorption (action on the principal cells of the late distal tubule and collecting duct)

b. ä renal K+ secretion (action on the principal cells of the late distal tubule and collecting duct)

c. ä renal H+ secretion (action on the α-intercalated cells of the late distal tubule and collecting duct)

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7-6

t a b l e

Pathophysiology of the Adrenal Cortex

Disorder

Clinical Features

ACTH Levels

Treatment

Addison’s disease (e.g., primary adrenocortical insufficiency)

Hypoglycemia Anorexia, weight loss, nausea, vomiting Weakness Hypotension Hyperkalemia Metabolic acidosis Decreased pubic and axillary hair in women Hyperpigmentation Hyperglycemia Muscle wasting Central obesity Round face, supraclavicular fat, buffalo hump Osteoporosis Striae Virilization and menstrual disorders in women Hypertension

Increased (negative feedback effect of decreased cortisol)

Replacement of glucocorticoids and mineralocorticoids

Decreased (negative feedback effect of increased cortisol)

Ketoconazole Metyrapone

Cushing’s syndrome (e.g., primary adrenal hyperplasia)

Cushing’s disease (excess ACTH) Conn’s syndrome (aldosteronesecreting tumor)

Same as Cushing’s syndrome Hypertension Hypokalemia Metabolic alkalosis Decreased renin

Increased

Surgical removal of ACTH-secreting tumor Spironolactone (aldosterone antagonist) Surgical removal of aldosteronesecreting tumor

21β-Hydroxylase deficiency (↓ glucocorticoids and mineralocorticoids; ↑ adrenal androgens)

Virilization of women Early acceleration of linear growth Early appearance of pubic and axillary hair Symptoms of glucocorticoid and mineralocorticoid deficiency Lack of pubic and axillary hair in women Symptoms of glucocorticoid deficiency Symptoms of mineralocorticoid excess


Replacement of glucocorticoids and mineralocorticoids


Replacement of glucocorticoids Aldosterone antagonist

17α-Hydroxylase deficiency (↓ adrenal androgens and glucocorticoids; ↑ mineralocorticoids)

See Table 7-1 for abbreviation.

5. Pathophysiology of the adrenal cortex (Table 7-6) a. Adrenocortical insufficiency (1) Primary adrenocortical insufficiency—Addison’s disease ■ ■

is most commonly caused by autoimmune destruction of the adrenal cortex and causes acute adrenal crisis. is characterized by the following:

(a) å adrenal glucocorticoid, androgen, and mineralocorticoid (b) ä ACTH (Low cortisol levels stimulate ACTH secretion by negative feedback.)

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241

(c) Hypoglycemia (caused by cortisol deficiency) (d) Weight loss, weakness, nausea, and vomiting (e) Hyperpigmentation (Low cortisol levels stimulate ACTH secretion; ACTH contains the MSH fragment.) (f) å pubic and axillary hair in women (caused by the deficiency of adrenal androgens) (g) ECF volume contraction, hypotension, hyperkalemia, and metabolic acidosis (caused by aldosterone deficiency) (2) Secondary adrenocortical insufficiency ■ ■ ■ ■

is caused by primary deficiency of ACTH. does not exhibit hyperpigmentation (because there is a deficiency of ACTH). does not exhibit volume contraction, hyperkalemia, or metabolic acidosis (because aldosterone levels are normal). Symptoms are otherwise similar to those of Addison’s disease.

b. Adrenocortical excess—Cushing’s syndrome ■ ■ ■ ■

is most commonly caused by the administration of pharmacologic doses of glucocorticoids. is also caused by primary hyperplasia of the adrenal glands. is called Cushing’s disease when it is caused by overproduction of ACTH. is characterized by the following:

(1) ä cortisol and androgen levels (2) å ACTH (if caused by primary adrenal hyperplasia or pharmacologic doses of

(3) (4) (5) (6) (7) (8) (9) (10) ■

glucocorticosteroids); ↑ ACTH (if caused by overproduction of ACTH, as in Cushing’s disease) Hyperglycemia (caused by elevated cortisol levels) ä protein catabolism and muscle wasting Central obesity (round face, supraclavicular fat, buffalo hump) Poor wound healing Virilization of women (caused by elevated levels of adrenal androgens) Hypertension (caused by elevated levels of cortisol and aldosterone) Osteoporosis (elevated cortisol levels cause increased bone resorption) Striae

Ketoconazole, an inhibitor of steroid hormone synthesis, can be used to treat Cushing’s disease.

c. Hyperaldosteronism—Conn’s syndrome ■ ■

is caused by an aldosterone-secreting tumor. is characterized by the following:

(1) Hypertension (because aldosterone increases Na+ reabsorption, which leads to increases in ECF volume and blood volume)

(2) Hypokalemia (because aldosterone increases K+ secretion) (3) Metabolic alkalosis (because aldosterone increases H+ secretion) (4) å renin secretion (because increased ECF volume and blood pressure inhibit renin secretion by negative feedback)

d. 21a-Hydroxylase deficiency ■ ■ ■

is the most common biochemical abnormality of the steroidogenic pathway (see Figure 7-11). belongs to a group of disorders characterized by adrenogenital syndrome. is characterized by the following:

(1) å cortisol and aldosterone levels (because the enzyme block prevents the production of 11-deoxycorticosterone and 11-deoxycortisol, the precursors for cortisol and aldosterone)

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(2) ↑ 17-hydroxyprogesterone and progesterone levels (because of accumulation of intermediates above the enzyme block)

(3) ä ACTH (because of decreased feedback inhibition by cortisol) (4) Hyperplasia of zona fasciculata and zona reticularis (because of high levels of ACTH)

(5) ä adrenal androgens (because 17-hydroxyprogesterone is their major precursor) and ä urinary 17-ketosteroids (6) Virilization in women (7) Early acceleration of linear growth and early appearance of pubic and axillary hair (8) Suppression of gonadal function in both men and women e. 17`-Hydroxylase deficiency is characterized by the following: (1) å androgen and glucocorticoid levels (because the enzyme block prevents the production of 17-hydroxypregnenolone and 17-hydroxyprogesterone)

(2) ä mineralocorticoid levels (because intermediates accumulate to the left of the enzyme block and are shunted toward the production of mineralocorticoids)

(3) Lack of pubic and axillary hair (which depends on adrenal androgens) in women (4) Hypoglycemia (because of decreased glucocorticoids) (5) Metabolic alkalosis, hypokalemia, and hypertension (because of increased mineralocorticoids

(6) ä ACTH (because decreased cortisol levels stimulate ACTH secretion by negative feedback)

B. Adrenal medulla (see Chapter 2 I A 4)

VI. ENDOCRINE PANCREAS—GLUCAGON AND INSULIN (TABLE 7-7) A. Organization of the endocrine pancreas ■ ■ ■

The islets of Langerhans contain three major cell types (Table 7-8). Other cells secrete pancreatic polypeptide. Gap junctions link beta cells to each other, alpha cells to each other, and beta cells to alpha cells for rapid communication. The portal blood supply of the islets allows blood from the beta cells (containing insulin) to bathe the alpha and delta cells, again for rapid cell-to-cell communication.

t a b l e

7-7

Comparison of Insulin and Glucagon Stimulus for Secretion

Insulin (tyrosine kinase receptor)

Glucagon (cAMP mechanism)

Major Actions

↑ Blood glucose ↑ Amino acids ↑ Fatty acids Glucagon GIP Growth hormone Cortisol

Increases glucose uptake into cells and glycogen formation Decreases glycogenolysis and gluconeogenesis Increases protein synthesis Increases fat deposition and decreases lipolysis Increases K+ uptake into cells

↓ Blood glucose ↑ Amino acids CCK Norepinephrine, epinephrine, ACh

Increases glycogenolysis and gluconeogenesis Increases lipolysis and ketoacid production

Overall Effect on Blood Levels ↓ [glucose]

↓ [amino acid] ↓ [fatty acid] ↓ [ketoacid] Hypokalemia ↑ [glucose] ↑ [fatty acid] ↑ [ketoacid]

ACh = acetylcholine; cAMP = cyclic adenosine monophosphate; CCK = cholecystokinin; GIP = glucose-dependent insulinotropic peptide.

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7-8

243

Cell Types of the Islets of Langerhans

Type of Cell

Location

Function

Beta Alpha Delta

Central islet Outer rim of islet Intermixed

Secrete insulin Secrete glucagon Secrete somatostatin and gastrin

B. Glucagon 1. Regulation of glucagon secretion (Table 7-9) ■

The major factor that regulates glucagon secretion is the blood glucose concentration. Decreased blood glucose stimulates glucagon secretion.

2. Actions of glucagon ■ ■

Glucagon acts on the liver and adipose tissue. The second messenger for glucagon is cAMP.

a. Glucagon increases the blood glucose concentration. (1) It increases glycogenolysis and prevents the recycling of glucose into glycogen. (2) It increases gluconeogenesis. Glucagon decreases the production of fructose 2,6bisphosphate, decreasing phosphofructokinase activity; in effect, substrate is directed toward glucose formation rather than toward glucose breakdown.

b. Glucagon increases blood fatty acid and ketoacid concentration. ■ ■

Glucagon increases lipolysis. The inhibition of fatty acid synthesis in effect “shunts” substrates toward gluconeogenesis. Ketoacids (β-hydroxybutyrate and acetoacetate) are produced from acetyl coenzyme A (CoA), which results from fatty acid degradation.

c. Glucagon increases urea production. ■

Amino acids are used for gluconeogenesis (stimulated by glucagon), and the resulting amino groups are incorporated into urea.

C. Insulin ■ ■

contains an A chain and a B chain, joined by two disulfide bridges. Proinsulin is synthesized as a single-chain peptide. Within storage granules, a connecting peptide (C peptide) is removed by proteases to yield insulin. The C peptide is packaged and secreted along with insulin, and its concentration is used to monitor beta cell function in diabetic patients who are receiving exogenous insulin.

1. Regulation of insulin secretion (Table 7-10) a. Blood glucose concentration ■

is the major factor that regulates insulin secretion. t a b l e

7-9

Regulation of Glucagon Secretion

Factors that Increase Glucagon Secretion

Factors that Decrease Glucagon Secretion

↓ Blood glucose ↑ Amino acids (especially arginine) CCK (alerts alpha cells to a protein meal) Norepinephrine, epinephrine ACh

↑ Blood glucose Insulin Somatostatin Fatty acids, ketoacids

ACh = acetylcholine; CCK = cholecystokinin.

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7-10

Regulation of Insulin Secretion

Factors that Increase Insulin Secretion

Factors that Decrease Insulin Secretion

↑ Blood glucose ↑ Amino acids (arginine, lysine, leucine) ↑ Fatty acids Glucagon GIP Ach

↓ Blood glucose Somatostatin Norepinephrine, epinephrine

ACh = acetylcholine; GIP = glucose-dependent insulinotropic peptide. ■

Increased blood glucose stimulates insulin secretion. An initial burst of insulin is followed by sustained secretion.

b. Mechanism of insulin secretion ■ ■

■

Glucose, the stimulant for insulin secretion, binds to the Glut 2 receptor on the beta cells. Inside the beta cells, glucose is oxidized to ATP, which closes K+ channels in the cell membrane and leads to depolarization of the beta cells. Similar to the action of ATP, sulfonylurea drugs (e.g., tolbutamide, glyburide) stimulate insulin secretion by closing these K+ channels. Depolarization opens Ca2+ channels, which leads to an increase in intracellular [Ca2+] and then to secretion of insulin.

2. Insulin receptor ■ ■

is found on target tissues for insulin. is a tetramer with two α subunits and two β subunits.

a. The a subunits span the cell membrane and have tyrosine kinase activity. When insulin binds to the receptor, tyrosine kinase autophosphorylates the β subunits. The phosphorylated receptor then phosphorylates intracellular proteins. b. The insulin-receptor complexes enter the target cells. c. Insulin down-regulates its own receptors in target tissues. ■

Therefore, the number of insulin receptors is increased in starvation and decreased in obesity.

3. Actions of insulin ■

Insulin acts on the liver, adipose tissue, and muscle.

a. Insulin decreases blood glucose concentration by the following mechanisms: (1) It increases uptake of glucose into target cells by directing the insertion of glucose transporters into cell membranes. As glucose enters the cells, the blood glucose concentration decreases. (2) It promotes formation of glycogen from glucose in muscle and liver, and simultaneously inhibits glycogenolysis. (3) It decreases gluconeogenesis. Insulin increases the production of fructose 2,6-bisphosphate, increasing phosphofructokinase activity. In effect, substrate is directed away from glucose formation.

b. Insulin decreases blood fatty acid and ketoacid concentrations. ■ ■

In adipose tissue, insulin stimulates fat deposition and inhibits lipolysis. Insulin inhibits ketoacid formation in the liver because decreased fatty acid degradation provides less acetyl CoA substrate for ketoacid formation.

c. Insulin decreases blood amino acid concentration. ■

Insulin stimulates amino acid uptake into cells, increases protein synthesis, and inhibits protein degradation. Thus, insulin is anabolic.

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245

d. Insulin decreases blood K+ concentration. ■

Insulin increases K+ uptake into cells, thereby decreasing blood [K+].

4. Insulin pathophysiology—diabetes mellitus ■

■

Case study: A woman is brought to the emergency room. She is hypotensive and breathing rapidly; her breath has the odor of ketones. Analysis of her blood shows severe hyperglycemia, hyperkalemia, and blood gas values that are consistent with metabolic acidosis. Explanation:

a. Hyperglycemia ■ ■ ■

is consistent with insulin deficiency. In the absence of insulin, glucose uptake into cells is decreased, as is storage of glucose as glycogen. If tests were performed, the woman’s blood would have shown increased levels of both amino acids (because of increased protein catabolism) and fatty acids (because of increased lipolysis).

b. Hypotension ■ ■ ■

is a result of ECF volume contraction. The high blood glucose concentration results in a high filtered load of glucose that exceeds the reabsorptive capacity (Tm) of the kidney. The unreabsorbed glucose acts as an osmotic diuretic in the urine and causes ECF volume contraction.

c. Metabolic acidosis ■ ■

is caused by overproduction of ketoacids (β-hydroxybutyrate and acetoacetate). The increased ventilation rate is the respiratory compensation for metabolic acidosis.

d. Hyperkalemia ■

results from the lack of insulin; normally, insulin promotes K+ uptake into cells.

D. Somatostatin ■ ■

is secreted by the delta cells of the pancreas. inhibits the secretion of insulin, glucagon, and gastrin.

VII. CALCIUM METABOLISM (PARATHYROID HORMONE, VITAMIN D, CALCITONIN) [TABLE 7-11] A. Overall Ca2+ homeostasis (Figure 7-13) ■ ■ ■ ■ ■

40% of the total Ca2+ in blood is bound to plasma proteins. 60% of the total Ca2+ in blood is not bound to proteins and is ultrafilterable. Ultrafilterable Ca2+ includes Ca2+ that is complexed to anions such as phosphate and free, ionized Ca2+. Free, ionized Ca2+ is biologically active. Serum [Ca2+] is determined by the interplay of intestinal absorption, renal excretion, and bone remodeling (bone resorption and formation). Each component is hormonally regulated. To maintain Ca2+ balance, net intestinal absorption must be balanced by urinary excretion.

1. Positive Ca2+ balance ■ ■

is seen in growing children. Intestinal Ca2+ absorption exceeds urinary excretion, and the excess is deposited in the growing bones.

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t a b l e

7-11

Stimulus for secretion

Action on: Bone Kidney

Intestine Overall effect on: Serum [Ca2+] Serum [phosphate]

Summary of Hormones that Regulate Ca2+ PTH

Vitamin D

Calcitonin

↓ Serum [Ca2+]

↓ Serum [Ca2+] ↑ PTH ↓ Serum [phosphate]

↑ Serum [Ca2+]

↑ Resorption ↓ P reabsorption (↑ urinary cAMP) ↑ Ca2+ reabsorption ↑ Ca2+ absorption (via activation of vitamin D)

↑ Resorption ↑ P reabsorption

↓ Resorption

↑ ↓

↑ ↑

↑ Ca2+ reabsorption ↑ Ca2+ absorption (calbindin D-28K) ↑ P absorption ↓

cAMP = cyclic adenosine monophosphate. See Table 7-1 for other abbreviation.

2. Negative Ca2+ balance ■ ■

is seen in women during pregnancy or lactation. Intestinal Ca2+ absorption is less than Ca2+ excretion, and the deficit comes from the maternal bones.

B. Parathyroid hormone (PTH) ■ ■

is the major hormone for the regulation of serum [Ca2+]. is synthesized and secreted by the chief cells of the parathyroid glands.

Ingested Ca2+ 1,25-Dihydroxycholecalciferol + Bone formation

Absorption ECF Ca2+ Secretion

Bone resorption

+ Filtration Fecal Ca2+

Reabsorption

– PTH, 1,25-Dihydroxycholecalciferol

+ PTH

Calcitonin

Urinary Ca2+ excretion

FIGURE 7-13 Hormonal regulation of Ca2+ metabolism. ECF = extracellular fluid; PTH = parathyroid hormone.

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247

1. Secretion of PTH ■

■ ■ ■ ■

is controlled by the serum [Ca2+] binding to Ca2+-sensing receptors in the parathyroid cell membrane. Decreased serum [Ca2+] increases PTH secretion, whereas increased serum Ca2+ decreases PTH secretion. Decreased serum Ca2+ causes decreased binding to the Ca2+-sensing receptor, which stimulates PTH secretion. Mild decreases in serum [Mg2+] stimulate PTH secretion. Severe decreases in serum [Mg2+] inhibit PTH secretion and produce symptoms of hypoparathyroidism (e.g., hypocalcemia). The second messenger for PTH secretion by the parathyroid gland is cAMP.

2. Actions of PTH ■ ■

are coordinated to produce an increase in serum [Ca2+] and a decrease in serum [phosphate]. The second messenger for PTH actions on its target tissues is cAMP.

a. PTH increases bone resorption, which brings both Ca2+ and phosphate from bone mineral into the ECF. Alone, this effect on bone would not increase the serum ionized [Ca2+] because phosphate complexes Ca2+. ■

Resorption of the organic matrix of bone is reflected in increased hydroxyproline excretion.

b. PTH inhibits renal phosphate reabsorption in the proximal tubule and, therefore, increases phosphate excretion (phosphaturic effect). As a result, the phosphate resorbed from bone is excreted in the urine, allowing the serum ionized [Ca2+] to increase. ■

cAMP generated as a result of the action of PTH on the proximal tubule is excreted in the urine (urinary cAMP).

c. PTH increases renal Ca2+ reabsorption in the distal tubule, which also increases the serum [Ca2+].

d. PTH increases intestinal Ca2+ absorption indirectly by stimulating the production of 1,25-dihydroxycholecalciferol in the kidney (see VII C).

3. Pathophysiology of PTH (Table 7-12) a. Primary hyperparathyroidism ■ ■

is most commonly caused by parathyroid adenoma. is characterized by the following:

(1) ↑ serum [Ca2+] (hypercalcemia) (2) ↓ serum [phosphate] (hypophosphatemia) (3) ↑ urinary phosphate excretion (phosphaturic effect of PTH) (4) ↑ urinary Ca2+ excretion (caused by the increased filtered load of Ca2+) (5) ↑ urinary cAMP (6) ↑ bone resorption b. Humoral hypercalcemia of malignancy ■

■

is caused by PTH-related peptide (PTH-rp) secreted by some malignant tumors (e.g., breast, lung). PTH-rp has all of the physiologic actions of PTH, including increased bone resorption, increased renal Ca2+ reabsorption, and decreased renal phosphate reabsorption. is characterized by the following:

(1) ↑ serum [Ca2+] (hypercalcemia) (2) ↓ serum [phosphate] (hypophosphatemia) (3) ↑ urinary phosphate excretion (phosphaturic effect of PTH-rp) (4) ↓ serum PTH levels (due to feedback inhibition from the high serum Ca2+) c. Hypoparathyroidism ■ ■

is most commonly a result of thyroid surgery, or it is congenital. is characterized by the following:

(1) ↓ serum [Ca2+] (hypocalcemia) and tetany

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7-12

t a b l e

Pathophysiology of PTH 1,25-Dihydroxycholecalciferol

Disorder

PTH

Primary hyperparathyroidism

↑

↑ (PTH stimulates ↑ Resorption 1α-hydroxylase)

Humoral hypercalcemia of malignancy

↓

—

↑ Resorption

↓

↓ Resorption

↓

↓ Resorption (defective Gs)

Surgical ↓ hypoparathyroidism Pseudohypoparathyroidism ↑

Chronic renal failure

Bone

Urine

Serum [Ca2+]

↑ P excretion ↑ (phosphaturia) ↑ Ca2+ excretion (high filtered load of Ca2+) ↑ urinary cAMP ↑ P excretion ↑ ↓ P excretion ↓ ↓ urinary cAMP ↓ P excretion ↓ ↓ urinary cAMP (defective Gs)

↑ (2º) ↓ (caused by renal Osteomalacia ↓ P excretion failure) (caused by (caused by ↓ 1,25↓ GFR) dihydroxycholecalciferol) ↑ Resorption (caused by ↑ PTH)

Serum [P] ↓

↓ ↑ ↑

↓ (caused by ↑ (caused ↓ 1,25by ↓ P dihydroxyexcretion) cholecalciferol)

cAMP = cyclic adenosine monophosphate; GFR = glomerular filtration rate. See Table 7-1 for other abbreviation.

(2) ↑ serum [phosphate] (hyperphosphatemia) (3) ↓ urinary phosphate excretion d. Pseudohypoparathyroidism type Ia—Albright’s hereditary osteodystrophy ■ ■ ■

is the result of defective Gs protein in kidney and bone, which causes end-organ resistance to PTH. Hypocalcemia and hyperphosphatemia occur (as in hypoparathyroidism), which are not correctable by the administration of exogenous PTH. Circulating PTH levels are elevated (stimulated by hypocalcemia).

e. Chronic renal failure ■ ■ ■ ■ ■

Decreased glomerular filtration rate (GFR) leads to decreased filtration of phosphate, phosphate retention, and increased serum [phosphate]. Increased serum phosphate complexes Ca2+ and leads to decreased ionized [Ca2+]. Decreased production of 1,25-dihydroxycholecalciferol by the diseased renal tissue also contributes to the decreased ionized [Ca2+] (see VII C 1). Decreased [Ca2+] causes secondary hyperparathyroidism. The combination of increased PTH levels and decreased 1,25-dihydroxycholecalciferol produces renal osteodystrophy, in which there is increased bone resorption and osteomalacia.

f. Familial hypocalciuric hypercalcemia (FHH) ■ ■

autosomal dominant disorder with decreased urinary Ca2+ excretion and increased serum Ca2+ caused by inactivating mutations of the Ca2+-sensing receptors that regulate PTH secretion.

C. Vitamin D ■ ■ ■

provides Ca2+ and phosphate to ECF for bone mineralization. In children, vitamin D deficiency causes rickets. In adults, vitamin D deficiency causes osteomalacia.

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Diet 7-Dehydrocholesterol

Cholecalciferol

Skin (ultraviolet)

Liver 25-OH-cholecalciferol [Ca2+] PTH

+

Kidney

[phosphate]

FIGURE 7-14 Steps and regulation in the synthesis of 1,25-dihydroxycholecalciferol. PTH = parathyroid hormone.

1,25-(OH)2-cholecalciferol

24,25-(OH)2-cholecalciferol

(active)

(inactive)

1. Vitamin D metabolism (Figure 7-14) ■ ■ ■ ■

Cholecalciferol, 25-hydroxycholecalciferol, and 24,25-dihydroxycholecalciferol are inactive. The active form of vitamin D is 1,25-dihydroxycholecalciferol. The production of 1,25-dihydroxycholecalciferol in the kidney is catalyzed by the enzyme 1α-hydroxylase. 1`-hydroxylase activity is increased by the following:

a. ↓ serum [Ca2+] b. ↑ PTH levels c. ↓ serum [phosphate] 2. Actions of 1,25-dihydroxycholecalciferol ■

are coordinated to increase both [Ca2+] and [phosphate] in ECF to mineralize new bone.

a. Increases intestinal Ca2+ absorption. Vitamin D–dependent Ca2+-binding protein (calbindin D-28K) is induced by 1,25-dihydroxycholecalciferol. ■

PTH increases intestinal Ca2+ absorption indirectly by stimulating 1α-hydroxylase and increasing production of the active form of vitamin D.

b. Increases intestinal phosphate absorption. c. Increases renal reabsorption of Ca2+ and phosphate, analogous to its actions on the intestine.

d. Increases bone resorption, which provides Ca2+ and phosphate from “old” bone to mineralize “new” bone.

D. Calcitonin ■ ■ ■ ■

is synthesized and secreted by the parafollicular cells of the thyroid. secretion is stimulated by an increase in serum [Ca2+]. acts primarily to inhibit bone resorption. can be used to treat hypercalcemia.

VIII. SEXUAL DIFFERENTIATION (FIGURE 7-15) ■ ■ ■

Genetic sex is defined by the sex chromosomes, XY in males and XX in females. Gonadal sex is defined by the presence of testes in males and ovaries in females. Phenotypic sex is defined by the characteristics of the internal genital tract and the external genitalia.

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Male

Female

XY

XX

Testes

Ovaries

Sertoli cells Antimüllerian hormone

Leydig cells Testosterone

Male phenotype

No antimüllerian hormone No testosterone

Female phenotype

FIGURE 7-15 Sexual differentiation in males and females.

A. Male phenotype ■ ■ ■

The testes of gonadal males secrete antimüllerian hormone and testosterone. Testosterone stimulates the growth and differentiation of the wolffian ducts, which develop into the male internal genital tract. Antimüllerian hormone causes atrophy of the müllerian ducts (which would have become the female internal genital tract).

B. Female phenotype ■ ■ ■

The ovaries of gonadal females secrete estrogen, but not antimüllerian hormone or testosterone. Without testosterone, the wolffian ducts do not differentiate. Without antimüllerian hormone, the müllerian ducts are not suppressed and therefore develop into the female internal genital tract.

IX. MALE REPRODUCTION A. Synthesis of testosterone (Figure 7-16) ■ ■

■ ■ ■

Testosterone is the major androgen synthesized and secreted by the Leydig cells. Leydig cells do not contain 21β-hydroxylase or 11β-hydroxylase (in contrast to the adrenal cortex) and, therefore, do not synthesize glucocorticoids or mineralocorticoids. LH (in a parallel action to ACTH in the adrenal cortex) increases testosterone synthesis by stimulating cholesterol desmolase, the first step in the pathway. Accessory sex organs (e.g., prostate) contain 5`-reductase, which converts testosterone to its active form, dihydrotestosterone. 5`-reductase inhibitors (finasteride) may be used to treat benign prostatic hyperplasia because they block the activation of testosterone to dihydrotestosterone in the prostate.

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Chapter 7 Endocrine Physiology Cholesterol

251

LH +

Pregnenolone



Androstenedione

17β-OH-steroid dehydrogenase

Testosterone FIGURE 7-16 Synthesis of testosterone. LH = luteinizing hormone.

Dihydrotestosterone

5α-reductase (target tissues)

B. Regulation of testes (Figure 7-17) 1. Hypothalamic control—GnRH ■

Arcuate nuclei of the hypothalamus secrete GnRH into the hypothalamic– hypophysial portal blood. GnRH stimulates the anterior pituitary to secrete FSH and LH.

2. Anterior pituitary—FSH and LH ■ ■

FSH acts on the Sertoli cells to maintain spermatogenesis. The Sertoli cells also secrete inhibin, which is involved in negative feedback of FSH secretion. LH acts on the Leydig cells to promote testosterone synthesis. Testosterone acts via an intratesticular paracrine mechanism to reinforce the spermatogenic effects of FSH in the Sertoli cells.

3. Negative feedback control—testosterone and inhibin ■ ■

Testosterone inhibits the secretion of LH by inhibiting the release of GnRH from the hypothalamus and by directly inhibiting the release of LH from the anterior pituitary. Inhibin (produced by the Sertoli cells) inhibits the secretion of FSH from the anterior pituitary.

C. Actions of testosterone or dihydrotestosterone 1. Actions of testosterone ■ ■ ■ ■ ■ ■ ■

Differentiation of epididymis, vas deferens, and seminal vesicles Pubertal growth spurt Cessation of pubertal growth spurt (epiphyseal closure) Libido Spermatogenesis in Sertoli cells (paracrine effect) Deepening of voice Increased muscle mass

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Hypothalamus (arcuate nucleus) –

GnRH +

Anterior pituitary –

–

LH

FSH +

Inhibin

+

Sertoli cells

Leydig cells +

Testosterone

Intratesticular

FIGURE 7-17 Control of male reproductive hormones. FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone.

■ ■

Growth of penis and seminal vesicles Negative feedback on anterior pituitary

2. Actions of dihydrotestosterone ■ ■ ■ ■ ■

Differentiation of penis, scrotum, and prostate Male hair pattern Male pattern baldness Sebaceous gland activity Growth of prostate

3. Androgen insensitivity disorder (testicular feminizing syndrome) ■ ■ ■ ■

is caused by deficiency of androgen receptors in target tissues of males. Testosterone and dihydrotestosterone actions in target tissues are absent. There are female external genitalia (“default”), and there is no internal genital tract. Testosterone levels are elevated due to lack of testosterone receptors in the anterior pituitary (lack of feedback inhibition).

D. Puberty (male and female) ■ ■ ■

is initiated by the onset of pulsatile GnRH release from the hypothalamus. FSH and LH are, in turn, secreted in pulsatile fashion. GnRH up-regulates its own receptor in the anterior pituitary.

E. Variation in FSH and LH levels over the life span (male and female) 1. In childhood, hormone levels are lowest and FSH > LH. 2. At puberty and during the reproductive years, hormone levels increase and LH > FSH.

3. In senescence, hormone levels are highest and FSH > LH.

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X. FEMALE REPRODUCTION A. Synthesis of estrogen and progesterone (Figure 7-18) ■

Theca cells produce testosterone (stimulated at the first step by LH). Androstenedione diffuses to the nearby granulosa cells, which contain 17β-hydroxysteroid dehydrogenase, which converts androstenedione to testosterone, and aromatase, which converts testosterone to 17β-estradiol (stimulated by FSH).

B. Regulation of the ovary 1. Hypothalamic control—GnRH ■

As in the male, pulsatile GnRH stimulates the anterior pituitary to secrete FSH and LH.

2. Anterior lobe of the pituitary—FSH and LH ■

FSH and LH stimulate the following in the ovaries:

a. Steroidogenesis in the ovarian follicle and corpus luteum b. Follicular development beyond the antral stage c. Ovulation d. Luteinization 3. Negative and positive feedback control—estrogen and progesterone (Table 7-13) C. Actions of estrogen 1. 2. 3. 4. 5.

Has both negative and positive feedback effects on FSH and LH secretion. Causes maturation and maintenance of the fallopian tubes, uterus, cervix, and vagina. Causes the development of female secondary sex characteristics at puberty. Causes the development of the breasts. Up-regulates estrogen, LH, and progesterone receptors. Cholesterol

LH (theca cells) +

Pregnenolone

Progesterone



Androstenedione

Testosterone aromatase

(granulosa cells) FIGURE 7-18 Synthesis of estrogen and progesterone. FSH = follicle-stimulating hormone; LH = luteinizing hormone.

17β-Estradiol

FSH +

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254


6. 7. 8. 9.

7-13

Negative and Positive Feedback Control of the Menstrual Cycle

Phase of Menstrual Cycle

Hormone

Type of Feedback and Site

Follicular Midcycle Luteal

Estrogen Estrogen Estrogen Progesterone

Negative; anterior pituitary Positive; anterior pituitary Negative; anterior pituitary Negative; anterior pituitary

Causes proliferation and development of ovarian granulosa cells. Maintains pregnancy. Lowers the uterine threshold to contractile stimuli during pregnancy. Stimulates prolactin secretion (but then blocks its action on the breast).

D. Actions of progesterone 1. 2. 3. 4. 5.

Has negative feedback effects on FSH and LH secretion during luteal phase. Maintains secretory activity of the uterus during the luteal phase. Maintains pregnancy. Raises the uterine threshold to contractile stimuli during pregnancy. Participates in development of the breasts.

E. Menstrual cycle (Figure 7-19) 1. Follicular phase (days 0–14) ■ ■ ■ ■ ■

A primordial follicle develops to the graafian stage, with atresia of neighboring follicles. LH and FSH receptors are up-regulated in theca and granulosa cells. Estradiol levels increase and cause proliferation of the uterus. FSH and LH levels are suppressed by the negative feedback effect of estradiol on the anterior pituitary. Progesterone levels are low.

2. Ovulation (day 14) ■ ■ ■ ■ ■

occurs 14 days before menses, regardless of cycle length. Thus, in a 28-day cycle, ovulation occurs on day 14; in a 35-day cycle, ovulation occurs on day 22. A burst of estradiol synthesis at the end of the follicular phase has a positive feedback effect on the secretion of FSH and LH (LH surge). Ovulation occurs as a result of the estrogen-induced LH surge. Estrogen levels decrease just after ovulation (but rise again during the luteal phase). Cervical mucus increases in quantity; it becomes less viscous and more penetrable by sperm.

3. Luteal phase (days 14–28) ■ ■ ■ ■

The corpus luteum begins to develop, and it synthesizes estrogen and progesterone. Vascularity and secretory activity of the endometrium increase to prepare for receipt of a fertilized egg. Basal body temperature increases because of the effect of progesterone on the hypothalamic thermoregulatory center. If fertilization does not occur, the corpus luteum regresses at the end of the luteal phase. As a result, estradiol and progesterone levels decrease abruptly.

4. Menses (days 0–4) ■

The endometrium is sloughed because of the abrupt withdrawal of estradiol and progesterone.

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Ovulation Follicular phase

Luteal phase

Basal body temperature

Progesterone

17β-Estradiol

LH

menses

FIGURE 7-19 The menstrual cycle. FSH = follicle-stimulating hormone; LH = luteinizing hormone.

FSH

menses

24 26 0 2 4 6 8 10 12 14 16 18 20 22 24 26 0 2 4 Day of cycle

F. Pregnancy (Figure 7-20) ■

is characterized by steadily increasing levels of estrogen and progesterone, which maintain the endometrium for the fetus, suppress ovarian follicular function (by inhibiting FSH and LH secretion), and stimulate development of the breasts.

1. Fertilization ■

If fertilization occurs, the corpus luteum is rescued from regression by human chorionic gonadotropin (HCG), which is produced by the placenta.

2. First trimester ■ ■

The corpus luteum (stimulated by HCG) is responsible for the production of estradiol and progesterone. Peak levels of HCG occur at gestational week 9 and then decline.

3. Second and third trimesters ■ ■

Progesterone is produced by the placenta. Estrogens are produced by the interplay of the fetal adrenal gland and the placenta. The fetal adrenal gland synthesizes dehydroepiandrosterone-sulfate (DHEA-S), which is then hydroxylated in the fetal liver. These intermediates are transferred to the placenta,

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L

Hormone level

HP

e

on

er

t es

og

Pr

l

trio

Es

10

Corpus luteum

■

20 30 Weeks of pregnancy

Placenta

40

FIGURE 7-20 Hormone levels during pregnancy. HCG = human chorionic gonadotropin; HPL = human placental lactogen.

where enzymes remove sulfate and aromatize to estrogens. The major placental estrogen is estriol. Human placental lactogen is produced throughout pregnancy. Its actions are similar to those of growth hormone and prolactin.

4. Parturition ■ ■ ■

Throughout pregnancy, progesterone increases the threshold for uterine contraction. Near term, the estrogen/progesterone ratio increases, which makes the uterus more sensitive to contractile stimuli. The initiating event in parturition is unknown. (Although oxytocin is a powerful stimulant of uterine contractions, blood levels of oxytocin do not change before labor.)

5. Lactation ■ ■ ■ ■ ■ ■

Estrogens and progesterone stimulate the growth and development of the breasts throughout pregnancy. Prolactin levels increase steadily during pregnancy because estrogen stimulates prolactin secretion from the anterior pituitary. Lactation does not occur during pregnancy because estrogen and progesterone block the action of prolactin on the breast. After parturition, estrogen and progesterone levels decrease abruptly and lactation occurs. Lactation is maintained by suckling, which stimulates both oxytocin and prolactin secretion. Ovulation is suppressed as long as lactation continues because prolactin has the following effects:

a. Inhibits hypothalamic GnRH secretion. b. Inhibits the action of GnRH on the anterior pituitary, and consequently inhibits LH and FSH secretion.

c. Antagonizes the actions of LH and FSH on the ovaries.

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Review Test Questions 1–5 Use the graph below, which shows changes during the menstrual cycle, to answer Questions 1–5.

A

B

C

D

3. The source of the increase in concentration indicated at point C is the (A) (B) (C) (D) (E)

hypothalamus anterior pituitary corpus luteum ovary adrenal cortex

4. The source of the increase in concentration at point D is the (A) (B) (C) (D) (E)

ovary adrenal cortex corpus luteum hypothalamus anterior pituitary

5. The cause of the sudden increase shown at point E is (A) negative feedback of progesterone on the hypothalamus

E

(B) negative feedback of estrogen on the anterior pituitary

(C) negative feedback of follicle-stimulating hormone (FSH) on the ovary

(D) positive feedback of FSH on the ovary (E) positive feedback of estrogen on the anterior pituitary 24 26 0 2 4 6 8 10 12 14 16 18 20 22 24 26 0 2 4 Day of cycle

1. The increase shown at point A is caused by the effect of (A) estrogen on the anterior pituitary (B) progesterone on the hypothalamus (C) follicle-stimulating hormone (FSH) on the ovary

(D) luteinizing hormone (LH) on the anterior pituitary

(E) prolactin on the ovary 2. Blood levels of which substance are described by curve B? (A) Estradiol (B) Estriol (C) Progesterone (D) Follicle-stimulating hormone (FSH) (E) Luteinizing hormone (LH)

6. A 41-year-old woman has hypocalcemia, hyperphosphatemia, and decreased urinary phosphate excretion. Injection of parathyroid hormone (PTH) causes an increase in urinary cyclic adenosine monophosphate (cAMP). The most likely diagnosis is (A) (B) (C) (D)

primary hyperparathyroidism vitamin D intoxication vitamin D deficiency hypoparathyroidism after thyroid surgery (E) pseudohypoparathyroidism

7. Which of the following hormones acts on its target tissues by a steroid hormone mechanism of action? (A) Thyroid hormone (B) Parathyroid hormone (PTH) (C) Antidiuretic hormone (ADH) on the collecting duct

257

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258


(D) β1 adrenergic agonists (E) Glucagon 8. A 38-year-old man who has galactorrhea is found to have a prolactinoma. His physician treats him with bromocriptine, which eliminates the galactorrhea. The basis for the therapeutic action of bromocriptine is that it (A) antagonizes the action of prolactin on the breast

(B) enhances the action of prolactin on the breast

(C) (D) (E) (F)

Puberty Somatomedins Starvation Hypoglycemia

13. Selective destruction of the zona glomerulosa of the adrenal cortex would produce a deficiency of which hormone?

(A) (B) (C) (D) (E)

Aldosterone Androstenedione Cortisol Dehydroepiandrosterone Testosterone

(C) inhibits prolactin release from the anterior pituitary

14. Which of the following explains the sup-

(D) inhibits prolactin release from the

pression of lactation during pregnancy?

hypothalamus (E) enhances the action of dopamine on the anterior pituitary

(A) Blood prolactin levels are too low for

9. Which of the following hormones origi-

(C) The fetal adrenal gland does not pro-

nates in the anterior pituitary?

(A) Dopamine (B) Growth hormone–releasing hormone (C) (D) (E) (F) (G)

(GHRH) Somatostatin Gonadotropin-releasing hormone (GnRH) Thyroid-stimulating hormone (TSH) Oxytocin Testosterone

10. Which of the following functions of the Sertoli cells mediates negative feedback control of follicle-stimulating hormone (FSH) secretion?

(A) (B) (C) (D)

Synthesis of inhibin Synthesis of testosterone Aromatization of testosterone Maintenance of the blood–testes barrier

11. Which of the following substances is derived from pro-opiomelanocortin (POMC)?

(A) (B) (C) (D) (E)

Adrenocorticotropic hormone (ACTH) Follicle-stimulating hormone (FSH) Melatonin Cortisol Dehydroepiandrosterone

12. Which of the following inhibits the secretion of growth hormone by the anterior pituitary?

(A) Sleep (B) Stress

milk production to occur

(B) Human placental lactogen levels are too low for milk production to occur duce sufficient estriol

(D) Blood levels of estrogen and progesterone are high

(E) The maternal anterior pituitary is suppressed

15. Which step in steroid hormone biosynthesis, if inhibited, blocks the production of all androgenic compounds but does not block the production of glucocorticoids?

(A) Cholesterol → pregnenolone (B) Progesterone → 11-deoxycorticosterone (C) 17-Hydroxypregnenolone → dehydroepiandrosterone

(D) Testosterone → estradiol (E) Testosterone → dihydrotestosterone 16. A 46-year-old woman has hirsutism, hyperglycemia, obesity, muscle wasting, and increased circulating levels of adrenocorticotropic hormone (ACTH). The most likely cause of her symptoms is

(A) primary adrenocortical insufficiency (Addison’s disease)

(B) pheochromocytoma (C) primary overproduction of ACTH (Cushing’s disease)

(D) treatment with exogenous glucocorticoids

(E) hypophysectomy 17. Which of the following decreases the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol?

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(A) (B) (C) (D) (E)

A diet low in Ca2+ Hypocalcemia Hyperparathyroidism Hypophosphatemia Chronic renal failure

18. Increased adrenocorticotropic hormone (ACTH) secretion would be expected in patients

(A) with chronic adrenocortical insufficiency (Addison’s disease)

(B) with primary adrenocortical hyperplasia (C) who are receiving glucocorticoid for immunosuppression after a renal transplant (D) with elevated levels of angiotensin II

19. Which of the following would be expect-

259

(D) Testosterone → estradiol (E) Testosterone → dihydrotestosterone 23. The source of estrogen during the second and third trimesters of pregnancy is the

(A) (B) (C) (D) (E) (F) (G)

corpus luteum maternal ovaries fetal ovaries placenta maternal ovaries and fetal adrenal gland maternal adrenal gland and fetal liver fetal adrenal gland, fetal liver, and placenta

24. Which of the following causes increased aldosterone secretion?

(A) Decreased blood volume (B) Administration of an inhibitor of

ed in a patient with Graves’ disease?

angiotensin-converting enzyme (ACE)

(A) (B) (C) (D) (E) (F) (G)

Cold sensitivity Weight gain Decreased O2 consumption Decreased cardiac output Drooping eyelids Atrophy of the thyroid gland Increased thyroid-stimulating hormone (TSH) levels (H) Increased triiodothyronine (T3) levels

(C) Hyperosmolarity (D) Hypokalemia

20. Blood levels of which of the following

26. Propylthiouracil can be used to reduce

substances is decreased in Graves’ disease?

the synthesis of thyroid hormones in hyperthyroidism because it inhibits oxidation of

(A) (B) (C) (D) (E)

Triiodothyronine (T3) Thyroxine (T4) Diiodotyrosine (DIT) Thyroid-stimulating hormone (TSH) Iodide (I–)

25. (A) (B) (C) (D) (E)

(A) (B) (C) (D) (E)

Secretion of oxytocin is increased by milk ejection dilation of the cervix increased prolactin levels increased extracellular fluid (ECF) volume increased serum osmolarity

Triiodothyronine (T3) Thyroxine (T4) Diiodotyrosine (DIT) Thyroid-stimulating hormone (TSH) Iodide (I–)

21. Which of the following hormones acts by an inositol 1,4,5-triphosphate (IP3)–Ca2+ mechanism of action?

(A) (B) (C) (D) (E)

1,25-Dihydroxycholecalciferol Progesterone Insulin Parathyroid hormone (PTH) Gonadotropin-releasing hormone (GnRH)

27. A 39-year-old man with untreated diabetes mellitus type I is brought to the emergency room. An injection of insulin would be expected to cause an increase in his

(A) (B) (C) (D) (E)

urine glucose concentration blood glucose concentration blood K+ concentration blood pH breathing rate

22. Which step in steroid hormone biosynthesis is stimulated by adrenocorticotropic hormone (ACTH)?


28. Which of the following results from the action of parathyroid hormone (PTH) on the renal tubule?

(A) Inhibition of 1α-hydroxylase (B) Stimulation of Ca2+ reabsorption in the distal tubule

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(C) Stimulation of phosphate reabsorption in the proximal tubule (D) Interaction with receptors on the luminal membrane of the proximal tubular cells (E) Decreased urinary excretion of cyclic adenosine monophosphate (cAMP)

29. Which step in steroid hormone biosynthesis occurs in the accessory sex target tissues of the male and is catalyzed by 5α-reductase?


(D) Testosterone → estradiol (E) Testosterone → dihydrotestosterone 30. Which of the following pancreatic secretions has a receptor with four subunits, two of which have tyrosine kinase activity?

(A) (B) (C) (D)

Insulin Glucagon Somatostatin Pancreatic lipase

31. A 16-year-old, seemingly normal female is diagnosed with androgen insensitivity disorder. She has never had a menstrual cycle and is found to have a blindending vagina; no uterus, cervix, or ovaries; a 46 XY genotype; and intraabdominal testes. Her serum testosterone is elevated. Which of the following characteristics is caused by lack of androgen receptors? (A) (B) (C) (D) (E)

46 XY genotype Testes Elevated serum testosterone Lack of uterus and cervix Lack of menstrual cycles

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Answers and Explanations 1. The answer is B [X E 3; Figure 7-19]. Curve A shows basal body temperature. The increase in temperature occurs as a result of elevated progesterone levels during the luteal (secretory) phase of the menstrual cycle. Progesterone increases the set-point temperature in the hypothalamic thermoregulatory center.

2. The answer is C [X E 3; Figure 7-19]. Progesterone is secreted during the luteal phase of the menstrual cycle.

3. The answer is D [X A, E 1; Figure 7-19]. The curve shows blood levels of estradiol. The source of the increase in estradiol concentration shown at point C is the ovarian granulosa cells, which contain high concentrations of aromatase and convert testosterone to estradiol.

4. The answer is C [X E 3; Figure 7-19]. The curve shows blood levels of estradiol. During the luteal phase of the cycle, the source of the estradiol is the corpus luteum. The corpus luteum prepares the uterus to receive a fertilized egg.

5. The answer is E [X E 2; Figure 7-20]. Point E shows the luteinizing hormone (LH) surge that initiates ovulation at midcycle. The LH surge is caused by increasing estrogen levels from the developing ovarian follicle. Increased estrogen, by positive feedback, stimulates the anterior pituitary to secrete LH and follicle-stimulating hormone (FSH).

6. The answer is D [VII B 3 b]. Low blood [Ca2+] and high blood [phosphate] are consistent with hypoparathyroidism. Lack of parathyroid hormone (PTH) decreases bone resorption, decreases renal reabsorption of Ca2+, and increases renal reabsorption of phosphate (causing low urinary phosphate). Because the patient responded to exogenous PTH with an increase in urinary cyclic adenosine monophosphate (cAMP), the G protein coupling the PTH receptor to adenylate cyclase is apparently normal. Consequently, pseudohypoparathyroidism is excluded. Vitamin D intoxication would cause hypercalcemia, not hypocalcemia. Vitamin D deficiency would cause hypocalcemia and hypophosphatemia.

7. The answer is A [II E; Table 7-2]. Thyroid hormone, an amine, acts on its target tissues by a steroid hormone mechanism, inducing the synthesis of new proteins. The action of antidiuretic hormone (ADH) on the collecting duct (V2 receptors) is mediated by cyclic adenosine monophosphate (cAMP), although the other action of ADH (vascular smooth muscle, V1 receptors) is mediated by inositol 1,4,5-triphosphate (IP3). Parathyroid hormone (PTH), β1 agonists, and glucagon all act through cAMP mechanisms of action.

8. The answer is C [III B 4 a (1), c (2)]. Bromocriptine is a dopamine agonist. The secretion of prolactin by the anterior pituitary is tonically inhibited by the secretion of dopamine from the hypothalamus. Thus, a dopamine agonist acts just like dopamine—it inhibits prolactin secretion from the anterior pituitary.

9. The answer is E [III B; Table 7-1]. Thyroid-stimulating hormone (TSH) is secreted by the anterior pituitary. Dopamine, growth hormone–releasing hormone (GHRH), somatostatin, and gonadotropin-releasing hormone (GnRH) all are secreted by the hypothalamus. Oxytocin is secreted by the posterior pituitary. Testosterone is secreted by the testes.

10. The answer is A [IX B 2, 3]. Inhibin is produced by the Sertoli cells of the testes when they are stimulated by follicle-stimulating hormone (FSH). Inhibin then inhibits further secretion of FSH by negative feedback on the anterior pituitary. The Leydig cells synthesize testosterone. Testosterone is aromatized in the ovaries.

261

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262


11. The answer is A [III B 1, 2; Figure 7-5]. Pro-opiomelanocortin (POMC) is the parent molecule in the anterior pituitary for adrenocorticotropic hormone (ACTH), β-endorphin, α-lipotropin, and β-lipotropin [and in the intermediary lobe for melanocyte-stimulating hormone (MSH)]. Follicle-stimulating hormone (FSH) is not a member of this “family”; rather, it is a member of the thyroid-stimulating hormone (TSH) and luteinizing hormone (LH) “family.” MSH, a component of POMC and ACTH, may stimulate melatonin production. Cortisol and dehydroepiandrosterone are produced by the adrenal cortex.

12. The answer is D [III B 3 a]. Growth hormone is secreted in pulsatile fashion, with a large burst occurring during deep sleep (sleep stage 3 or 4). Growth hormone secretion is increased by sleep, stress, puberty, starvation, and hypoglycemia. Somatomedins are generated when growth hormone acts on its target tissues; they inhibit growth hormone secretion by the anterior pituitary, both directly and indirectly (by stimulating somatostatin release).

13. The answer is A [V A 1; Figure 7-10]. Aldosterone is produced in the zona glomerulosa of the adrenal cortex because that layer contains the enzyme for conversion of corticosterone to aldosterone (aldosterone synthase). Cortisol is produced in the zona fasciculata. Androstenedione and dehydroepiandrosterone are produced in the zona reticularis. Testosterone is produced in the testes, not in the adrenal cortex.

14. The answer is D [X F 5]. Although the high circulating levels of estrogen stimulate prolactin secretion during pregnancy, the action of prolactin on the breast is inhibited by progesterone and estrogen. After parturition, progesterone and estrogen levels decrease dramatically. Prolactin can then interact with its receptors in the breast, and lactation proceeds if initiated by suckling.

15. The answer is C [Figure 7-11]. The conversion of 17-hydroxypregnenolone to dehydroepiandrosterone (as well as the conversion of 17-hydroxyprogesterone to androstenedione) is catalyzed by 17,20-lyase. If this process is inhibited, synthesis of androgens is stopped.

16. The answer is C [V A 5 b]. This woman has the classic symptoms of a primary elevation of adrenocorticotropic hormone (ACTH) [Cushing’s disease]. Elevation of ACTH stimulates overproduction of glucocorticoids and androgens. Treatment with pharmacologic doses of glucocorticoids would produce similar symptoms, except that circulating levels of ACTH would be low because of negative feedback suppression at both the hypothalamic [corticotropin-releasing hormone (CRH)] and anterior pituitary (ACTH) levels. Addison’s disease is caused by primary adrenocortical insufficiency. Although a patient with Addison’s disease would have increased levels of ACTH (because of the loss of negative feedback inhibition), the symptoms would be of glucocorticoid deficit, not excess. Hypophysectomy would remove the source of ACTH. A pheochromocytoma is a tumor of the adrenal medulla that secretes catecholamines.

17. The answer is E [VII C 1]. Ca2+ deficiency (low Ca2+ diet or hypocalcemia) activates 1α-hydroxylase, which catalyzes the conversion of vitamin D to its active form, 1,25-dihydroxycholecalciferol. Increased parathyroid hormone (PTH) and hypophosphatemia also stimulate the enzyme. Chronic renal failure is associated with a constellation of bone diseases, including osteomalacia caused by failure of the diseased renal tissue to produce the active form of vitamin D.

18. The answer is A [V A 2 a (3); Table 7-6; Figure 7-12]. Addison’s disease is caused by primary adrenocortical insufficiency. The resulting decrease in cortisol production causes a decrease in negative feedback inhibition on the hypothalamus and the anterior pituitary. Both of these conditions will result in increased adrenocorticotropic hormone (ACTH) secretion. Patients who have adrenocortical hyperplasia or who are receiving exogenous glucocorticoid will have an increase in the negative feedback inhibition of ACTH secretion.

19. The answer is H [IV B 2; Table 7-5]. Graves’ disease (hyperthyroidism) is caused by overstimulation of the thyroid gland by circulating antibodies to the thyroid-stimulating

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263

hormone (TSH) receptor [which then increases the production and secretion of triiodothyronine (T3) and thyroxine (T4), just as TSH would]. Therefore, the signs and symptoms of Graves’ disease are the same as those of hyperthyroidism, reflecting the actions of increased circulating levels of thyroid hormones: increased heat production, weight loss, increased O2 consumption and cardiac output, exophthalmos (bulging eyes, not drooping eyelids), and hypertrophy of the thyroid gland (goiter). TSH levels will be decreased (not increased) as a result of the negative feedback effect of increased T3 levels on the anterior pituitary.

20. The answer is D [IV B 2; Table 7-5]. In Graves’ disease (hyperthyroidism), the thyroid is stimulated to produce and secrete vast quantities of thyroid hormones as a result of stimulation by thyroid-stimulating immunoglobulins [antibodies to the thyroid-stimulating hormone (TSH) receptors on the thyroid gland]. Because of the high circulating levels of thyroid hormones, anterior pituitary secretion of TSH will be turned off (negative feedback).

21. The answer is E [Table 7-2]. Gonadotropin-releasing hormone (GnRH) is a peptide hormone that acts on the cells of the anterior pituitary by an inositol 1,4,5-triphosphate (IP3)–Ca2+ mechanism to cause the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). 1,25-Dihydroxycholecalciferol and progesterone are steroid hormone derivatives of cholesterol that act by inducing the synthesis of new proteins. Insulin acts on its target cells by a tyrosine kinase mechanism. Parathyroid hormone (PTH) acts on its target cells by an adenylate cyclase–cyclic adenosine monophosphate (cAMP) mechanism.

22. The answer is A [V A 2 a (2)]. The conversion of cholesterol to pregnenolone is catalyzed by cholesterol desmolase. This step in the biosynthetic pathway for steroid hormones is stimulated by adrenocorticotropic hormone (ACTH).

23. The answer is G [X F 3]. During the second and third trimesters of pregnancy, the fetal adrenal gland synthesizes dehydroepiandrosterone-sulfate (DHEA-S), which is hydroxylated in the fetal liver and then transferred to the placenta, where it is aromatized to estrogen. In the first trimester, the corpus luteum is the source of both estrogen and progesterone.

24. The answer is A [V A 2 b]. Decreased blood volume stimulates the secretion of renin (because of decreased renal perfusion pressure) and initiates the renin–angiotensin– aldosterone cascade. Angiotensin-converting enzyme (ACE) inhibitors block the cascade by decreasing the production of angiotensin II. Hyperosmolarity stimulates antidiuretic hormone (ADH) [not aldosterone] secretion. Hyperkalemia, not hypokalemia, directly stimulates aldosterone secretion by the adrenal cortex.

25. The answer is B [III C 2]. Suckling and dilation of the cervix are the physiologic stimuli for oxytocin secretion. Milk ejection is the result of oxytocin action, not the cause of its secretion. Prolactin secretion is also stimulated by suckling, but prolactin does not directly cause oxytocin secretion. Increased extracellular fluid (ECF) volume and hyperosmolarity are the stimuli for the secretion of the other posterior pituitary hormone, antidiuretic hormone (ADH).

26. The answer is E [IV A 2]. For iodide (I–) to be “organified” (incorporated into thyroid hormone), it must be oxidized to I2, which is accomplished by a peroxidase enzyme in the thyroid follicular cell membrane. Propylthiouracil inhibits peroxidase and, therefore, halts the synthesis of thyroid hormones.

27. The answer is D [VI C 3; Table 7-7]. Before the injection of insulin, the woman would have had hyperglycemia, glycosuria, hyperkalemia, and metabolic acidosis with compensatory hyperventilation. The injection of insulin would be expected to decrease her blood glucose (by increasing the uptake of glucose into the cells), decrease her urinary glucose (secondary to decreasing her blood glucose), decrease her blood K+ (by shifting K+ into the cells), and correct her metabolic acidosis (by decreasing the production of ketoacids).

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Board Review Series: Physiology The correction of the metabolic acidosis will lead to an increase in her blood pH and will reduce her compensatory hyperventilation.

28. The answer is B [VII B 2]. Parathyroid hormone (PTH) stimulates both renal Ca2+ reabsorption in the renal distal tubule and the 1α-hydroxylase enzyme. PTH inhibits (not stimulates) phosphate reabsorption in the proximal tubule, which is associated with an increase in urinary cyclic adenosine monophosphate (cAMP). The receptors for PTH are located on the basolateral membranes, not the luminal membranes.

29. The answer is E [IX A]. Some target tissues for androgens contain 5α-reductase, which converts testosterone to dihydrotestosterone, the active form in those tissues.

30. The answer is A [VI C 2]. The insulin receptor in target tissues is a tetramer. The two β subunits have tyrosine kinase activity and autophosphorylate the receptor when stimulated by insulin.

31. The answer is C [IX C]. The elevated serum testosterone is due to lack of androgen receptors on the anterior pituitary (which normally would mediate negative feedback by testosterone). The presence of testes is due to the male genotype. The lack of uterus and cervix is due to antimüllerian hormone (secreted by the fetal testes), which suppressed differentiation of the müllerian ducts into the internal female genital tract. The lack of menstrual cycles is due to the absence of a female reproductive tract.


Comprehensive Examination Questions 1 and 2 After extensive testing, a 60-year-old man is found to have a pheochromocytoma that secretes mainly epinephrine.

1. Which of the following signs would be expected in this patient? (A) Decreased heart rate (B) Decreased arterial blood pressure (C) Decreased excretion rate of 3-methoxy-

(A) administration of digitalis (B) administration of a negative inotropic agent

(C) increased blood volume (D) decreased blood volume (E) decreased total peripheral resistance (TPR)

Questions 5 and 6

B

100

2. Symptomatic treatment would be best achieved in this man with (A) phentolamine (B) isoproterenol (C) a combination of phentolamine and isoproterenol

(D) a combination of phentolamine and propranolol

Hemoglobin saturation (%)

4-hydroxymandelic acid (VMA) (D) Cold, clammy skin

A

50

(E) a combination of isoproterenol and phenylephrine

3. The principle of positive feedback is

25

illustrated by the effect of

(A) PO2 on breathing rate (B) glucose on insulin secretion (C) estrogen on follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion in midcycle (D) blood [Ca2+] on parathyroid hormone (PTH) secretion (E) decreased blood pressure on sympathetic outflow to the heart and blood vessels

4. In the graph at upper right, the response shown by the dotted line illustrates the effect of


Cardiac output

50 75 PO2 (mm Hg)

100

5. On the accompanying graph, the shift from curve A to curve B could be caused by (A) (B) (C) (D) (E)

fetal hemoglobin (HbF) carbon monoxide (CO) poisoning decreased pH increased temperature increased 2,3-diphosphoglycerate (DPG)

6. The shift from curve A to curve B is associated with (A) decreased P50 (B) decreased affinity of hemoglobin for O2 (C) decreased O2-carrying capacity of hemoglobin

(D) increased ability to unload O2 in the tissues 7. A negative free-water clearance (CH2O) would occur in a person

Ve

no

us

re

tu

rn

Right atrial pressure (mm Hg) or end-diastolic volume (L)

(A) who drinks 2 L of water in 30 minutes (B) after overnight water restriction (C) who is receiving lithium for the treatment of depression and has polyuria that is unresponsive to antidiuretic hormone (ADH) administration

265


266


(D) with a urine flow rate of 5 mL/min, a urine osmolarity of 295 mOsm/L, and a serum osmolarity of 295 mOsm/L (E) with a urine osmolarity of 90 mOsm/L and a serum osmolarity of 310 mOsm/L after a severe head injury

(B) increased circulating levels of aldosterone

(C) inhibition of the action of ADH on the renal tubule

(D) stimulation of the action of ADH on the renal tubule

(E) psychogenic water drinking 8. CO2 generated in the tissues is carried in venous blood primarily as

13. The treatment drug is administered in

(A) (B) (C) (D) (E)

error and produces a further increase in the patient’s serum [Ca2+]. That drug is

CO2 in the plasma H2CO3 in the plasma HCO3− in the plasma CO2 in the red blood cells (RBCs) carboxyhemoglobin in the RBCs

9. In a 35-day menstrual cycle, ovulation occurs on day (A) (B) (C) (D) (E)

12 14 17 21 28

10. Which of the following hormones stimulates the conversion of testosterone to 17βestradiol in ovarian granulosa cells?

(A) (B) (C) (D) (E) (F) (G)

Adrenocorticotropic hormone (ACTH) Estradiol Follicle-stimulating hormone (FSH) Gonadotropin-releasing hormone (GnRH) Human chorionic gonadotropin (HCG) Prolactin Testosterone

11. Which gastrointestinal secretion is hypo-

(A) (B) (C) (D) (E)

a thiazide diuretic a loop diuretic calcitonin mithramycin etidronate disodium

14. Which of the following substances acts on its target cells via an inositol 1,4,5triphosphate (IP3)–Ca2+ mechanism?

(A) Somatomedins acting on chondrocytes (B) Oxytocin acting on myoepithelial cells of the breast

(C) Antidiuretic hormone (ADH) acting on the renal collecting duct

(D) Adrenocorticotropic hormone (ACTH) acting on the adrenal cortex

(E) Thyroid hormone acting on skeletal muscle

15. A key difference in the mechanism of excitation–contraction coupling between the muscle of the pharynx and the muscle of the wall of the small intestine is that

tonic, has a high [HCO3−], and has its production inhibited by vagotomy?

(A) slow waves are present in the pharynx,

(A) (B) (C) (D)

for contraction in the pharynx, but not in the small intestine (C) intracellular [Ca2+] is increased after excitation in the pharynx, but not in the small intestine (D) action potentials depolarize the muscle of the small intestine, but not of the pharynx (E) Ca2+ binds to troponin C in the pharynx, but not in the small intestine, to initiate contraction

Saliva Gastric secretion Pancreatic secretion Bile

Questions 12 and 13 A 53-year-old man with multiple myeloma is hospitalized after 2 days of polyuria, polydipsia, and increasing confusion. Laboratory tests show an elevated serum [Ca2+] of 15 mg/dL, and treatment is initiated to decrease it. The patient’s serum osmolarity is 310 mOsm/L.

12. The most likely reason for polyuria in this man is

(A) increased circulating levels of antidiuretic hormone (ADH)

but not in the small intestine

(B) adenosine triphosphate (ATP) is used

16. A 40-year-old woman has an arterial pH of 7.25, an arterial PCO2 of 30 mm Hg, and serum [K+] of 2.8 mEq/L. Her blood pressure is 100/80 mm Hg when supine and 80/50 mm Hg when standing. What is the cause of her abnormal blood values?


267

Chapter 8 Comprehensive Examination Vomiting Diarrhea Treatment with a loop diuretic Treatment with a thiazide diuretic

17. Secretion of HCl by gastric parietal cells is needed for

(A) (B) (C) (D) (E)

activation of pancreatic lipases activation of salivary lipases activation of intrinsic factor activation of pepsinogen to pepsin the formation of micelles

18. Which of the following would cause an

plasma [glucose] < 200 mg/dL, curves X and Z are superimposed on each other because

X Glucose filtration, excretion, reabsorption (mg/min)

(A) (B) (C) (D)

Y

Z

increase in glomerular filtration rate (GFR)?

(A) (B) (C) (D) (E) 19. (A) (B) (C) (D) (E)

Constriction of the afferent arteriole Constriction of the efferent arteriole Constriction of the ureter Increased plasma protein concentration Infusion of inulin Fat absorption occurs primarily in the stomach jejunum terminal ileum cecum sigmoid colon

20. Which of the following hormones causes constriction of vascular smooth muscle through an inositol 1,4,5-triphosphate (IP3) second messenger system?

(A) (B) (C) (D) (E)

Antidiuretic hormone (ADH) Aldosterone Dopamine Oxytocin Parathyroid hormone (PTH)

21. A 30-year-old woman has the anterior lobe of her pituitary gland surgically removed because of a tumor. Without hormone replacement therapy, which of the following would occur after the operation?

0

200

400

600

800

Plasma [glucose] (mg/dL)

(A) the reabsorption and excretion of glucose are equal

(B) all of the filtered glucose is reabsorbed (C) glucose reabsorption is saturated (D) the renal threshold for glucose has been exceeded

(E) Na+–glucose cotransport has been inhibited

(F) All of the filtered glucose is excreted 23. Which of the following responses occurs as a result of tapping on the patellar tendon?

(A) Stimulation of Ib afferent fibers in the muscle spindle

(B) Inhibition of Ia afferent fibers in the muscle spindle

(C) Relaxation of the quadriceps muscle (D) Contraction of the quadriceps muscle (E) Inhibition of α-motoneurons Questions 24 and 25 A 5-year-old boy has a severe sore throat, high fever, and cervical adenopathy.

(A) Absence of menses (B) Inability to concentrate the urine in

24. It is suspected that the causative agent is

response to water deprivation (C) Failure to secrete catecholamines in response to stress (D) Failure to secrete insulin in a glucose tolerance test (E) Failure to secrete parathyroid hormone (PTH) in response to hypocalcemia

(A) Increased production of interleukin-1

Streptococcus pyogenes. Which of the following is involved in producing fever in this patient? (IL-1)

(B) Decreased production of prostaglandins (C) Decreased set-point temperature in the hypothalamus

22. The following graph shows three relationships as a function of plasma [glucose]. At

(D) Decreased metabolic rate (E) Vasodilation of blood vessels in the skin


268


25. Before antibiotic therapy is initiated, the patient is given aspirin to reduce his fever. The mechanism of fever reduction by aspirin is

(A) (B) (C) (D)

shivering stimulation of cyclooxygenase inhibition of prostaglandin synthesis shunting of blood from the surface of the skin (E) increasing the hypothalamic set-point temperature

26. Arterial pH of 7.52, arterial PCO2 of 26 mm Hg, and tingling and numbness in the feet and hands would be observed in a (A) patient with chronic diabetic ketoacidosis (B) patient with chronic renal failure (C) patient with chronic emphysema and bronchitis

(A) (B) (C) (D) (E) (F) (G)

Atrial systole Isovolumetric ventricular contraction Rapid ventricular ejection Reduced ventricular ejection Isovolumetric ventricular relaxation Rapid ventricular filling Reduced ventricular filling

Questions 31 and 32 A 17-year-old boy is brought to the emergency department after being injured in an automobile accident and sustaining significant blood loss. He is given a transfusion of 3 units of blood to stabilize his blood pressure.

31. Before the transfusion, which of the following was true about his condition?

(A) His total peripheral resistance (TPR) was decreased

(D) patient who hyperventilates on a commuter flight (E) patient who is taking a carbonic anhydrase inhibitor for glaucoma (F) patient with a pyloric obstruction who vomits for 5 days (G) healthy person

(B) His heart rate was decreased (C) The firing rate of his carotid sinus

27. Albuterol is useful in the treatment of

the decrease in blood volume in this patient?

asthma because it acts as an agonist at which of the following receptors?

(A) Increased renal perfusion pressure (B) Increased circulating levels of

(A) (B) (C) (D) (E)

α1 Receptor β1 Receptor β2 Receptor Muscarinic receptor Nicotinic receptor

28. Which of the following hormones is converted to its active form in target tissues by the action of 5α-reductase?

(A) (B) (C) (D) (E)

Adrenocorticotropic hormone (ACTH) Aldosterone Estradiol Prolactin Testosterone

29. If an artery is partially occluded by an embolism such that its radius becomes onehalf the preocclusion value, which of the following parameters will increase by a factor of 16?

(A) (B) (C) (D)

Blood flow Resistance Pressure gradient Capacitance

30. If heart rate increases, which phase of the cardiac cycle is decreased?

nerves was increased

(D) Sympathetic outflow to his heart and blood vessels was increased

32. Which of the following is a consequence of

angiotensin II

(C) Decreased renal Na+ reabsorption (D) Decreased renal K+ secretion 33. A 37-year-old woman suffers a severe head injury in a skiing accident. Shortly thereafter, she becomes polydipsic and polyuric. Her urine osmolarity is 75 mOsm/L, and her serum osmolarity is 305 mOsm/L. Treatment with 1-deamino-8-D-arginine vasopressin (dDAVP) causes an increase in her urine osmolarity to 450 mOsm/L. Which diagnosis is correct?

(A) (B) (C) (D) (E)

Primary polydipsia Central diabetes insipidus Nephrogenic diabetes insipidus Water deprivation Syndrome of inappropriate antidiuretic hormone (SIADH)

34. Which diuretic inhibits Na+ reabsorption

and K+ secretion in the distal tubule by acting as an aldosterone antagonist?

(A) (B) (C) (D)

Acetazolamide Chlorothiazide Furosemide Spironolactone


Chapter 8 Comprehensive Examination

35. Which gastrointestinal secretion has a component that is required for the intestinal absorption of vitamin B12?

(A) (B) (C) (D)


269

40. Phase 2, the plateau phase, of the action potential shown

(A) is the result of Ca2+ flux out of the cell (B) increases in duration as heart rate increases

(C) corresponds to the effective refractory period

(D) is the result of approximately equal inward and outward currents

36. Secretion of which of the following hormones is stimulated by extracellular fluid volume expansion?

(A) (B) (C) (D) (E)

Antidiuretic hormone (ADH) Aldosterone Atrial natriuretic peptide (ANP) 1,25-Dihydroxycholecalciferol Parathyroid hormone (PTH)

to which portion of an electrocardiogram (ECG)?

thetic pathway is stimulated by angiotensin II? Aldosterone synthase Aromatase Cholesterol desmolase 17,20-Lyase 5α-Reductase

2

Millivolts

3

(A) patient with chronic diabetic keto-

–60 –80

acidosis 4

–100 100 msec

38. (A) (B) (C) (D) (E)

Iodide (I−) pump I− → I2 I2 + tyrosine Diiodotyrosine (DIT) + DIT Thyroxine (T4) → triiodothyronine (T3)

14 mEq/L, increased urinary excretion of NH4+, and hyperventilation would be observed in a

–20 0

(A) (B) (C) (D) (E)

43. Arterial pH of 7.29, arterial [HCO3−] of

0

–40

P wave PR interval QRS complex ST segment QT interval

the biosynthetic pathway for thyroid hormones that is inhibited by propylthiouracil?

Use the diagram of an action potential to answer the following questions. 1

(A) (B) (C) (D) (E)

42. Which of the following is the first step in

Questions 38–41

+20

when another action potential can most easily be elicited

41. The action potential shown corresponds

37. Which step in the steroid hormone syn(A) (B) (C) (D) (E)

(E) is the portion of the action potential

The action potential shown is from a skeletal muscle cell a smooth muscle cell a sinoatrial (SA) cell an atrial muscle cell a ventricular muscle cell

(B) patient with chronic renal failure (C) patient with chronic emphysema and bronchitis

(D) patient who hyperventilates on a commuter flight

(E) patient who is taking a carbonic anhydrase inhibitor for glaucoma

(F) patient with a pyloric obstruction who vomits for 5 days

(G) healthy person 44. Activation of which of the following

39. Phase 0 of the action potential shown is produced by an

(A) (B) (C) (D) (E)

inward K+ current inward Na+ current inward Ca2+ current outward Na+ current outward Ca2+ current

receptors increases total peripheral resistance (TPR)?

(A) (B) (C) (D) (E)



270


45. The receptor for this hormone has tyrosine kinase activity.

(A) (B) (C) (D) (E) (F)

Adrenocorticotropic hormone (ACTH) Antidiuretic hormone (ADH) Aldosterone Insulin Parathyroid hormone (PTH) Somatostatin

46. If an artery is partially occluded by an embolism such that its radius becomes onehalf the preocclusion value, which of the following parameters will decrease by a factor of 16?

(A) (B) (C) (D)


47. Which phase of the cardiac cycle is absent if there is no P wave on the electrocardiogram (ECG)?

(A) (B) (C) (D) (E) (F) (G)


48. A receptor potential in the pacinian corpuscle

(A) is all-or-none (B) has a stereotypical size and shape (C) is the action potential of this sensory receptor (D) if hyperpolarizing, increases the likelihood of action potential occurrence (E) if depolarizing, brings the membrane potential closer to threshold

49. Compared with the base of the lung, in a person who is standing, the apex of the lung has

(A) (B) (C) (D) (E)

a higher ventilation rate a higher perfusion rate a higher ventilation/perfusion (V/Q) ratio the same V/Q ratio a lower pulmonary capillary PO2

50. A 54-year-old man with a lung tumor has high circulating levels of antidiuretic hormone (ADH), a serum osmolarity of 260 mOsm/L, and a negative free-water

clearance (CH2O). Which diagnosis is correct?

(A) (B) (C) (D) (E)


51. End-organ resistance to which of the following hormones results in polyuria and elevated serum osmolarity?

(A) (B) (C) (D) (E)

Antidiuretic hormone (ADH) Aldosterone 1,25-Dihydroxycholecalciferol Parathyroid hormone (PTH) Somatostatin

52. Which diuretic causes increased urinary

excretion of Na+ and K+ and decreased urinary excretion of Ca2+?

(A) (B) (C) (D)


53. Arterial PCO2 of 72 mm Hg, arterial [HCO3−] of 38 mEq/L, and increased H+ excretion would be observed in a (A) patient with chronic diabetic ketoacidosis





(G) healthy person 54. In a skeletal muscle capillary, the capillary hydrostatic pressure (Pc) is 32 mm Hg, the capillary oncotic pressure (πc) is 27 mm Hg, and the interstitial hydrostatic pressure (Pi) is 2 mm Hg. Interstitial oncotic pressure (πi) is negligible. What is the driving force across the capillary wall, and will it favor filtration or absorption?

(A) (B) (C) (D) (E)

3 mm Hg, favoring absorption 3 mm Hg, favoring filtration 7 mm Hg, favoring absorption 7 mm Hg, favoring filtration 9 mm Hg, favoring filtration



271

55. Which of the following substances has

61. Inhibition of which step in the steroid

the lowest renal clearance?

hormone synthetic pathway blocks the production of all androgenic compounds in the adrenal cortex, but not the production of glucocorticoids or mineralocorticoids?

(A) (B) (C) (D) (E)

Creatinine Glucose K+ Na+ Para-aminohippuric acid (PAH)

56. Atropine causes dry mouth by inhibiting which of the following receptors?

(A) (B) (C) (D) (E)


(A) (B) (C) (D) (E)

Aldosterone synthase Aromatase Cholesterol desmolase 17,20-Lyase 5α-Reductase

62. Arterial pH of 7.54, arterial [HCO3−] of

48 mEq/L, hypokalemia, and hypoventilation would be observed in a

(A) patient with chronic diabetic ketoacidosis

57. Which of the following transport mechanisms is inhibited by furosemide in the thick ascending limb?

(A) (B) (C) (D) (E)

Na+ diffusion via Na+ channels Na+–glucose cotransport (symport) Na+–K+–2Cl− cotransport (symport) Na+–H+ exchange (antiport) Na+,K+-adenosine triphosphatase (ATPase)





(G) healthy person 58. Which of the following conditions decreases the likelihood of edema formation?

(A) (B) (C) (D) (E)

Arteriolar constriction Venous constriction Standing Nephrotic syndrome Inflammation

63. Somatostatin inhibits the secretion of which of the following hormones?

(A) (B) (C) (D) (E)

Antidiuretic hormone (ADH) Insulin Oxytocin Prolactin Thyroid hormone

59. Which of the following conditions causes hypoventilation?

(A) (B) (C) (D) (E)

Strenuous exercise Ascent to high altitude Anemia Diabetic ketoacidosis Chronic obstructive pulmonary disease (COPD)

64. Which of the following substances is converted to a more active form after its secretion?

(A) (B) (C) (D) (E)

Testosterone Triiodothyronine (T3) Reverse triiodothyronine (rT3) Angiotensin II Aldosterone

60. A 28-year-old man who is receiving

65. Levels of which of the following hor-

lithium treatment for bipolar disorder becomes polyuric. His urine osmolarity is 90 mOsm/L; it remains at that level when he is given a nasal spray of dDAVP. Which diagnosis is correct?

mones are high during the first trimester of pregnancy and decline during the second and third trimesters?

(A) (B) (C) (D) (E)


(A) (B) (C) (D) (E) (F) (G) (H)

Adrenocorticotropic hormone (ACTH) Estradiol Follicle-stimulating hormone (FSH) Gonadotropin-releasing hormone (GnRH) Human chorionic gonadotropin (HCG) Oxytocin Prolactin Testosterone


272


The following diagram applies to Questions 66 and 67. C

68. At which site is the amount of paraaminohippuric acid (PAH) in tubular fluid lowest?

(A) (B) (C) (D) (E)

69. At which site is the creatinine concentra-

D

A

E

B


tion highest in a person who is deprived of water?

(A) (B) (C) (D) (E)


66. During which labeled wave or segment of the electrocardiogram (ECG) are both the atria and the ventricles completely repolarized?

70. At which site is the tubular fluid [HCO3−] highest?

(A) (B) (C) (D) (E)

(A) (B) (C) (D) (E)

A B C D E

67. During which labeled wave or segment


71. At which site is the amount of K+ in

of the electrocardiogram (ECG) is aortic pressure at its lowest value?

tubular fluid lowest in a person who is on a very low K+ diet?

(A) (B) (C) (D) (E)

(A) (B) (C) (D) (E)

A B C D E

The following diagram applies to Questions 68–74. A B D


72. At which site is the composition of tubular fluid closest to that of plasma?

(A) (B) (C) (D) (E)


73. At which site is about one-third of the filtered water remaining in the tubular fluid?

(A) (B) (C) (D) (E)


74. At which site is the tubular fluid osmoE C

larity lower than the plasma osmolarity in a person who is deprived of water?

(A) Site A (B) Site B



(C) Site C (D) Site D (E) Site E 75. A patient’s electrocardiogram (ECG) shows periodic QRS complexes that are not preceded by P waves and that have a bizarre shape. These QRS complexes originated in the

(A) (B) (C) (D)

sinoatrial (SA) node atrioventricular (AV) node His-Purkinje system ventricular muscle

273

81. During which phase of the cardiac cycle does ventricular pressure rise, but ventricular volume remain constant?

(A) (B) (C) (D) (E) (F) (G)


82. Which of the following lung volumes or capacities includes the residual volume?

76. Which of the following substances would be expected to cause an increase in arterial blood pressure?

(A) (B) (C) (D) (E)

Saralasin V1 agonist Acetylcholine (ACh) Spironolactone Phenoxybenzamine

77. A decrease in which of the following parameters in an artery will produce an increase in pulse pressure?

(A) (B) (C) (D)


(A) (B) (C) (D) (E)

Tidal volume (TV) Vital capacity (VC) Inspiratory capacity (IC) Functional residual capacity (FRC) Inspiratory reserve volume (IRV)

83. Arterial [HCO3−] of 18 mEq/L, PCO2 of 34 mm Hg, and increased urinary HCO3− excretion would be observed in a

(A) patient with chronic diabetic ketoacidosis (B) patient with chronic renal failure (C) patient with chronic emphysema and bronchitis



78. Which of the following changes occurs

(F) patient with a pyloric obstruction who

during moderate exercise?

(A) Increased total peripheral resistance (B) (C) (D) (E)

(TPR) Increased stroke volume Decreased pulse pressure Decreased venous return Decreased arterial PO2

79. Plasma renin activity is lower than normal in patients with

(A) (B) (C) (D)

hemorrhagic shock essential hypertension congestive heart failure hypertension caused by aortic constriction above the renal arteries

80. Inhibition of which enzyme in the steroid hormone synthetic pathway reduces the size of the prostate?

(A) (B) (C) (D) (E)


vomits for 5 days

(G) healthy person 84. Bromocriptine reduces galactorrhea by acting as an agonist for which of the following substances?

(A) (B) (C) (D)

Dopamine Estradiol Follicle-stimulating hormone (FSH) Gonadotropin-releasing hormone (GnRH) (E) Human chorionic gonadotropin (HCG) (F) Oxytocin (G) Prolactin

85. A 32-year-old woman who is thirsty has a urine osmolarity of 950 mOsm/L and a serum osmolarity of 297 mOsm/L. Which diagnosis is correct?

(A) (B) (C) (D) (E)



274


86. Hypoxia causes vasoconstriction in

91. Which gastrointestinal secretion is inhib-

which of the following vascular beds?

ited when the pH of the stomach contents is 1.0?

(A) (B) (C) (D) (E)

Cerebral Coronary Muscle Pulmonary Skin

87. Which diuretic is administered for the

(A) (B) (C) (D)


92. Which of the following would be expect-

treatment of acute mountain sickness and causes an increase in the pH of urine?

ed to increase after surgical removal of the duodenum?

(A) (B) (C) (D)

(A) (B) (C) (D) (E)


88. Arterial pH of 7.25, arterial PCO2 of 30 mm Hg, and decreased urinary excretion of NH4+ would be observed in a (A) patient with chronic diabetic ketoacidosis


(D) patient who hyperventilates on a commuter flight (E) patient who is taking a carbonic anhydrase inhibitor for glaucoma (F) patient with a pyloric obstruction who vomits for 5 days (G) healthy person

89. In which of the following situations will arterial PO2 be closest to 100 mm Hg?

(A) A person who is having a severe asthmatic attack

(B) A person who lives at high altitude (C) A person who has a right-to-left cardiac shunt (D) A person who has a left-to-right cardiac shunt (E) A person who has pulmonary fibrosis

Gastric emptying Secretion of cholecystokinin (CCK) Secretion of secretin Contraction of the gallbladder Absorption of lipids

93. Which of the following hormones causes contraction of vascular smooth muscle?

(A) (B) (C) (D) (E)

Antidiuretic hormone (ADH) Aldosterone Atrial natriuretic peptide (ANP) 1,25-Dihydroxycholecalciferol Parathyroid hormone (PTH)

94. Which of the following is absorbed by facilitated diffusion?

(A) (B) (C) (D) (E) (F)

Glucose in duodenal cells Fructose in duodenal cells Dipeptides in duodenal cells Vitamin B1 in duodenal cells Cholesterol in duodenal cells Bile acids in ileal cells

95. Which of the following hormones acts on the anterior lobe of the pituitary to inhibit secretion of growth hormone?

(A) Dopamine (B) Gonadotropin-releasing hormone (GnRH)

(C) Insulin (D) Prolactin (E) Somatostatin

90. Which of the following is an example of a primary active transport process?

96. Which step in the steroid hormone syn-

(A) Na+–glucose transport in small intestin-

thetic pathway is required for the development of female secondary sex characteristics, but not male secondary sex characteristics?

(B) (C) (D) (E)

al epithelial cells Na+–alanine transport in renal proximal tubular cells Insulin-dependent glucose transport in muscle cells H+–K+ transport in gastric parietal cells Na+–Ca2+ exchange in nerve cells

(A) (B) (C) (D) (E)




97. At the beginning of which phase of the

(C) Cyclic guanosine monophosphate

cardiac cycle does the second heart sound occur?

(D) All-trans rhodopsin is converted to

(A) (B) (C) (D) (E) (F) (G)


98. Which of the following actions occurs when light strikes a photoreceptor cell of the retina?

(A) Transducin is inhibited (B) The photoreceptor depolarizes

275

(cGMP) levels in the cell decrease 11-cis rhodopsin

(E) An excitatory neurotransmitter is released

99. Which step in the biosynthetic pathway for thyroid hormones produces thyroxine (T4)?

(A) (B) (C) (D) (E)

Iodide (I−) pump I− → I2 I2 + tyrosine Diiodotyrosine (DIT) + DIT DIT + monoiodotyrosine (MIT)


Answers and Explanations 1. The answer is D [Chapter 2 I C; Table 2-2]. Increased circulating levels of epinephrine from the adrenal medullary tumor stimulate both α-adrenergic and β-adrenergic receptors. Thus, heart rate and contractility are increased and, as a result, cardiac output is increased. Total peripheral resistance (TPR) is increased because of arteriolar vasoconstriction, which leads to decreased blood flow to the cutaneous circulation and causes cold, clammy skin. Together, the increases in cardiac output and TPR increase arterial blood pressure. 3-Methoxy-4-hydroxymandelic acid (VMA) is a metabolite of both norepinephrine and epinephrine; increased VMA excretion occurs in pheochromocytomas.

2. The answer is D [Chapter 2 I; Table 2-3]. Treatment is directed at blocking both the α-stimulatory and β-stimulatory effects of catecholamines. Phentolamine is an α-blocking agent; propranolol is a β-blocking agent. Isoproterenol is a β1 and β2 agonist. Phenylephrine is an α1 agonist.

3. The answer is C [Chapter 7 I D; X E 2]. The effect of estrogen on the secretion of folliclestimulating hormone (FSH) and luteinizing hormone (LH) by the anterior lobe of the pituitary gland at midcycle is one of the few examples of positive feedback in physiologic systems—increasing estrogen levels at midcycle cause increased secretion of FSH and LH. The other options illustrate negative feedback. Decreased arterial PO2 causes an increase in breathing rate (via peripheral chemoreceptors). Increased blood glucose stimulates insulin secretion. Decreased blood [Ca2+] causes an increase in parathyroid hormone (PTH) secretion. Decreased blood pressure decreases the firing rate of carotid sinus nerves (via the baroreceptors) and ultimately increases sympathetic outflow to the heart and blood vessels to return blood pressure to normal.

4. The answer is B [Chapter 3 IV F 3 a; Figures 3-8 and 3-12]. A downward shift of the cardiac output curve is consistent with decreased myocardial contractility (negative inotropism); for any right atrial pressure or end-diastolic volume, the force of contraction is decreased. Digitalis, a positive inotropic agent, would produce an upward shift of the cardiac output curve. Changes in blood volume alter the venous return curve rather than the cardiac output curve. Changes in total peripheral resistance (TPR) alter both the cardiac output and venous return curves.

5. The answer is A [Chapter 4 IV A 2, C; Figure 4-7]. Because fetal hemoglobin (HbF) has a greater affinity for O2 than does adult hemoglobin, the O2–hemoglobin dissociation curve would shift to the left. Carbon monoxide poisoning would cause a shift to the left, but would also cause a decrease in total O2-carrying capacity (decreased percent saturation) because CO occupies O2-binding sites. Decreased pH, increased temperature, and increased 2,3-diphosphoglycerate (DPG) all would shift the curve to the right.

6. The answer is A [Chapter 4 IV C 2]. A shift to the left of the O2–hemoglobin dissociation

curve represents an increased affinity of hemoglobin for O2. Accordingly, at any given level of PO2, the percent saturation is increased, the P50 is decreased (read the PO2 at 50% saturation), and the ability to unload O2 to the tissues is impaired (because of the higher affinity of hemoglobin for O2). The O2-carrying capacity is determined by hemoglobin concentration and is unaffected by the shift from curve A to curve B.

7. The answer is B [Chapter 5 VII D; Table 5-6]. A person with a negative free-water clearance (CH2O) would, by definition, be producing urine that is hyperosmotic to blood (CH2O = V − Cosm). After overnight water restriction, serum osmolarity increases. This increase, via hypothalamic osmoreceptors, stimulates the release of antidiuretic hormone (ADH) from the posterior lobe of the pituitary. This ADH circulates to the collecting ducts of the

276



277

kidney and causes reabsorption of water, which results in the production of hyperosmotic urine. Drinking large amounts of water inhibits the secretion of ADH and causes excretion of dilute urine and a positive CH2O. Lithium causes nephrogenic diabetes insipidus by blocking the response of ADH on the collecting duct cells, resulting in dilute urine and a positive CH2O. In option D, the calculated value of CH2O is zero. In option E, the calculated value of CH2O is positive.

8. The answer is C [Chapter 4 V B; Figure 4-9]. CO2 generated in the tissues enters venous

blood and, in the red blood cells (RBCs), combines with H2O in the presence of carbonic anhydrase to form H2CO3. H2CO3 dissociates into H+ and HCO3−. The H+ remains in the RBCs to be buffered by deoxyhemoglobin, and the HCO3− moves into plasma in exchange for Cl−. Thus, CO2 is carried in venous blood to the lungs as HCO3−. In the lungs, the reactions occur in reverse: CO2 is regenerated and expired.

9. The answer is D [Chapter 7 X E 2]. Menses occurs 14 days after ovulation, regardless of cycle length. Therefore, in a 35-day menstrual cycle, ovulation occurs on day 21. Ovulation occurs at the midpoint of the menstrual cycle only if the cycle length is 28 days.

10. The answer is C [Chapter 7 X A]. Testosterone is synthesized from cholesterol in ovarian theca cells and diffuses to ovarian granulosa cells, where it is converted to estradiol by the action of aromatase. Follicle-stimulating hormone (FSH) stimulates the aromatase enzyme and increases the production of estradiol.

11. The answer is A [Chapter 6 IV A 2–4 a]. Saliva has a high [HCO3−] because the cells lining the salivary ducts secrete HCO3−. Because the ductal cells are relatively impermeable to water and because they reabsorb more solute (Na+ and Cl−) than they secrete (K+ and HCO3−), the saliva is rendered hypotonic. Vagal stimulation increases saliva production, so vagotomy (or atropine) inhibits it and produces dry mouth.

12. The answer is C [Chapter 5 VII D 3; Table 5-6]. The most likely explanation for this patient’s polyuria is hypercalcemia. With severe hypercalcemia, Ca2+ accumulates in the inner medulla and papilla of the kidney and inhibits adenylate cyclase, blocking the effect of ADH on water permeability. Because ADH is ineffective, the urine cannot be concentrated and the patient excretes large volumes of dilute urine. His polydipsia is secondary to his polyuria, and is caused by the increased serum osmolarity. Psychogenic water drinking would also cause polyuria, but the serum osmolarity would be lower than normal, not higher than normal.

13. The answer is A [Chapter 5 VI C]. Thiazide diuretics would be contraindicated in a patient with severe hypercalcemia because these drugs cause increased Ca2+ reabsorption in the renal distal tubule. On the other hand, loop diuretics inhibit Ca2+ and Na+ reabsorption and produce calciuresis. When given with fluid replacement, loop diuretics can effectively and rapidly lower the serum [Ca2+]. Calcitonin, mithramycin, and etidronate disodium inhibit bone resorption and, as a result, decrease serum [Ca2+].

14. The answer is B [Chapter 7; Table 7-2]. Oxytocin causes contraction of the myoepithelial cells of the breast by an inositol 1,4,5-triphosphate (IP3)–Ca2+ mechanism. Somatomedins [insulin-like growth factor (IGF)], like insulin, act on target cells by activating tyrosine kinase. Antidiuretic hormone (ADH) acts on the V2 receptors of the renal collecting duct by a cyclic adenosine monophosphate (cAMP) mechanism (although in vascular smooth muscle it acts on V1 receptors by an IP3 mechanism). Adrenocorticotropic hormone (ACTH) also acts via a cAMP mechanism. Thyroid hormone induces the synthesis of new protein [e.g., Na+,K+-adenosine triphosphatase (ATPase)] by a steroid hormone mechanism.

15. The answer is E [Chapter 1 VI B; VII B; Table 1-3]. The pharynx is skeletal muscle, and the small intestine is unitary smooth muscle. The difference between smooth and skeletal muscle is the mechanism by which Ca2+ initiates contraction. In smooth muscle, Ca2+ binds to calmodulin, and in skeletal muscle, Ca2+ binds to troponin C. Both types of muscle are excited to contract by action potentials. Slow waves are present in


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Board Review Series: Physiology smooth muscle, but not skeletal muscle. Both smooth and skeletal muscle require an increase in intracellular [Ca2+] as the important linkage between excitation (the action potential) and contraction, and both consume adenosine triphosphate (ATP) during contraction.

16. The answer is B [Chapter 5 IX D; Table 5-9]. The arterial blood values and physical findings are consistent with metabolic acidosis, hypokalemia, and orthostatic hypotension. Diarrhea is associated with the loss of HCO3− and K+ from the gastrointestinal (GI) tract, consistent with the laboratory values. Hypotension is consistent with extracellular fluid (ECF) volume contraction. Vomiting would cause metabolic alkalosis and hypokalemia. Treatment with loop or thiazide diuretics could cause volume contraction and hypokalemia, but would cause metabolic alkalosis rather than metabolic acidosis.

17. The answer is D [Chapter 6 V B 1 c]. Pepsinogen is secreted by the gastric chief cells and is activated to pepsin by the low pH of the stomach (created by secretion of HCl by the gastric parietal cells). Lipases are inactivated by low pH.

18. The answer is B [Chapter 5 II C 6; Table 5-3]. Glomerular filtration rate (GFR) is determined by the balance of Starling forces across the glomerular capillary wall. Constriction of the efferent arteriole increases the glomerular capillary hydrostatic pressure (because blood is restricted in leaving the glomerular capillary), thus favoring filtration. Constriction of the afferent arteriole would have the opposite effect and would reduce the glomerular capillary hydrostatic pressure. Constriction of the ureter would increase the hydrostatic pressure in the tubule and, therefore, oppose filtration. Increased plasma protein concentration would increase the glomerular capillary oncotic pressure and oppose filtration. Infusion of inulin is used to measure the GFR and does not alter the Starling forces.

19. The answer is B [Chapter 6 V C 1, 2]. First, fat absorption requires the breakdown of dietary lipids to fatty acids, monoglycerides, and cholesterol in the duodenum by pancreatic lipases. Second, fat absorption requires the presence of bile acids, which are secreted into the small intestine by the gallbladder. These bile acids form micelles around the products of lipid digestion and deliver them to the absorbing surface of the small intestinal cells. Because the bile acids are recirculated to the liver from the ileum, fat absorption must be complete before the chyme reaches the terminal ileum.

20. The answer is A [Chapter 7 III C 1 b]. Antidiuretic hormone (ADH) causes constriction of vascular smooth muscle by activating a V1 receptor that uses the inositol 1,4,5triphosphate (IP3) and Ca2+ second messenger system. When hemorrhage or extracellular fluid (ECF) volume contraction occurs, ADH secretion by the posterior pituitary is stimulated via volume receptors. The resulting increase in ADH levels causes increased water reabsorption by the collecting ducts (V2 receptors) and vasoconstriction (V1 receptors) to help restore blood pressure.

21. The answer is A [Chapter 7 III B]. Normal menstrual cycles depend on the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. Concentration of urine in response to water deprivation depends on the secretion of antidiuretic hormone (ADH) by the posterior pituitary. Catecholamines are secreted by the adrenal medulla in response to stress, but anterior pituitary hormones are not involved. Anterior pituitary hormones are not involved in the direct effect of glucose on the beta cells of the pancreas or in the direct effect of Ca2+ on the chief cells of the parathyroid gland.

22. The answer is B [Chapter 5 III B]. Curves X, Y, and Z show glucose filtration, glucose excretion, and glucose reabsorption, respectively. Below a plasma [glucose] of 200 mg/dL, the carriers for glucose reabsorption are unsaturated, so all of the filtered glucose can be reabsorbed, and none will be excreted in the urine.

23. The answer is D [Chapter 2 III C 1; Figure 2-9]. When the patellar tendon is stretched, the quadriceps muscle also stretches. This movement activates Ia afferent fibers of the



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muscle spindles, which are arranged in parallel formation in the muscle. These Ia afferent fibers form synapses on α-motoneurons in the spinal cord. In turn, the pool of α-motoneurons is activated and causes reflex contraction of the quadriceps muscle to return it to its resting length.

24. The answer is A [Chapter 2 VI C]. Streptococcus pyogenes causes increased production of interleukin-1 (IL-1) in macrophages. IL-1 acts on the anterior hypothalamus to increase the production of prostaglandins, which increase the hypothalamic set-point temperature. The hypothalamus then “reads” the core temperature as being lower than the new set-point temperature, and activates various heat-generating mechanisms that increase body temperature (fever). These mechanisms include shivering and vasoconstriction of blood vessels in the skin.

25. The answer is C [Chapter 2 VI C 2]. By inhibiting cyclooxygenase, aspirin inhibits the production of prostaglandins and lowers the hypothalamic set-point temperature to its original value. After aspirin treatment, the hypothalamus “reads” the body temperature as being higher than the set-point temperature and activates heat-loss mechanisms, including sweating and vasodilation of skin blood vessels. This vasodilation shunts blood toward the surface skin. When heat is lost from the body by these mechanisms, body temperature is reduced.

26. The answer is D [Chapter 5 IX D 4; Table 5-9]. The blood values are consistent with acute respiratory alkalosis from hysterical hyperventilation. The tingling and numbness are symptoms of a reduction in serum ionized [Ca2+] that occurs secondary to alkalosis. Because of the reduction in [H+], fewer H+ ions will bind to negatively charged sites on plasma proteins, and more Ca2+ binds (decreasing the free ionized [Ca2+]).

27. The answer is C [Chapter 2 I C 1 d]. Albuterol is an adrenergic β2 agonist. When activated, the β2 receptors in the bronchioles produce bronchodilation.

28. The answer is E [Chapter 7 IX A; Figure 7-16]. Testosterone is converted to its active form, dihydrotestosterone, in some target tissues by the action of 5α-reductase.

29. The answer is B [Chapter 3 II C, D]. A decrease in radius causes an increase in resistance, as described by the Poiseuille relationship (resistance is inversely proportional to r4). Thus, if radius decreases twofold, the resistance will increase by (2)4, or 16-fold.

30. The answer is G [Chapter 3 V; Figure 3-15]. When heart rate increases, the time between ventricular contractions (for refilling of the ventricles with blood) decreases. Because most ventricular filling occurs during the “reduced” phase, this phase is the most compromised by an increase in heart rate.

31. The answer is D [Chapter 3 IX C; Table 3-6; Figure 3-21]. The blood loss that occurred in the accident caused a decrease in arterial blood pressure. The decrease in arterial pressure was detected by the baroreceptors in the carotid sinus and caused a decrease in the firing rate of the carotid sinus nerves. As a result of the baroreceptor response, sympathetic outflow to the heart and blood vessels increased, and parasympathetic outflow to the heart decreased. Together, these changes caused an increased heart rate, increased contractility, and increased total peripheral resistance (TPR) [in an attempt to restore the arterial blood pressure].

32. The answer is B [Chapter 3 IX C; Table 3-6; Figure 3-21; Chapter 5 IV C 3 b (1)]. The decreased blood volume causes decreased renal perfusion pressure, which initiates a cascade of events, including increased renin secretion, increased circulating angiotensin II, increased aldosterone secretion, increased Na+ reabsorption, and increased K+ secretion by the renal tubule.

33. The answer is B [Chapter 5 VII C; Table 5-6]. A history of head injury with production of dilute urine accompanied by elevated serum osmolarity suggests central diabetes insipidus. The response of the kidney to exogenous antidiuretic hormone (ADH) [1-deamino-8-D-arginine vasopressin (dDAVP)] eliminates nephrogenic diabetes insipidus as the cause of the concentrating defect.


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34. The answer is D [Chapter 5 IV C 3 b (1); Table 5-11]. Spironolactone inhibits distal tubule Na+ reabsorption and K+ secretion by acting as an aldosterone antagonist.

35. The answer is B [Chapter 6 V E 1 c; Table 6-3]. Gastric parietal cells secrete intrinsic factor, which is required for the intestinal absorption of vitamin B12.

36. The answer is C [Chapter 3 VI C 4]. Atrial natriuretic peptide (ANP) is secreted by the atria in response to extracellular fluid volume expansion and subsequently acts on the kidney to cause increased excretion of Na+ and H2O.

37. The answer is A [Chapter 7 V A 2 b; Figure 7-11]. Angiotensin II increases production of aldosterone by stimulating aldosterone synthase, the enzyme that catalyzes the conversion of corticosterone to aldosterone.

38. The answer is E [Chapter 3 III B; Figures 3-4 and 3-5]. The action potential shown is characteristic of ventricular muscle, with a stable resting membrane potential and a long plateau phase of almost 300 msec. Action potentials in skeletal cells are much shorter (only a few milliseconds). Smooth muscle action potentials would be superimposed on fluctuating baseline potentials (slow waves). Sinoatrial (SA) cells of the heart have spontaneous depolarization (pacemaker activity) rather than a stable resting potential. Atrial muscle cells of the heart have a much shorter plateau phase and a much shorter overall duration.

39. The answer is B [Chapter 3 III B 1 a]. Depolarization, as in phase 0, is caused by an inward current (defined as the movement of positive charge into the cell). The inward current during phase 0 of the ventricular muscle action potential is caused by opening of Na+ channels in the ventricular muscle cell membrane, movement of Na+ into the cell, and depolarization of the membrane potential toward the Na+ equilibrium potential (approximately +65 mV). In sinoatrial (SA) cells, phase 0 is caused by an inward Ca2+ current.

40. The answer is D [Chapter 3 III B 1 c]. Because the plateau phase is a period of stable membrane potential, by definition, the inward and outward currents are equal and balance each other. Phase 2 is the result of opening of Ca2+ channels and inward, not outward, Ca2+ current. In this phase, the cells are refractory to the initiation of another action potential. Phase 2 corresponds to the absolute refractory period, rather than the effective refractory period (which is longer than the plateau). As heart rate increases, the duration of the ventricular action potential decreases, primarily by decreasing the duration of phase 2.

41. The answer is E [Chapter 3 III A 4; Figure 3-3]. The action potential shown represents both depolarization and repolarization of a ventricular muscle cell. Therefore, on an electrocardiogram (ECG), it corresponds to the period of depolarization (beginning with the Q wave) through repolarization (completion of the T wave). That period is defined as the QT interval.

42. The answer is B [Chapter 7 IV A 2]. The oxidation of I− to I2 is catalyzed by peroxidase and inhibited by propylthiouracil, which can be used in the treatment of hyperthyroidism. Later steps in the pathway that are catalyzed by peroxidase and inhibited by propylthiouracil are iodination of tyrosine, coupling of diiodotyrosine (DIT) and DIT, and coupling of DIT and monoiodotyrosine (MIT).

43. The answer is A [Chapter 5 IX D 1; Table 5-9]. The blood values are consistent with metabolic acidosis, as would occur in diabetic ketoacidosis. Hyperventilation is the respiratory compensation for metabolic acidosis. Increased urinary excretion of NH4+ reflects the adaptive increase in NH3 synthesis that occurs in chronic acidosis. Patients with metabolic acidosis secondary to chronic renal failure would have reduced NH4+ excretion (because of diseased renal tissue).

44. The answer is A [Chapter 2 I C 1 a]. When adrenergic α1 receptors on the vascular smooth muscle are activated, they cause vasoconstriction and increased total peripheral resistance (TPR).



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45. The answer is D [Chapter 7; Table 7-2]. Hormone receptors with tyrosine kinase activity include those for insulin and for insulin-like growth factors (IGF). The β subunits of the insulin receptor have tyrosine kinase activity and, when activated by insulin, the receptors autophosphorylate. The phosphorylated receptors then phosphorylate intracellular proteins; this process ultimately results in the physiologic actions of insulin.

46. The answer is A [Chapter 3 II C, D]. Blood flow through the artery is proportional to the pressure difference and inversely proportional to the resistance (Q = ΔP/R). Because resistance increased 16-fold when the radius decreased twofold, blood flow must decrease 16-fold.

47. The answer is A [Chapter 3 V; Figure 3-15]. The P wave represents electrical activation (depolarization) of the atria. Atrial contraction is always preceded by electrical activation.

48. The answer is E [Chapter 2 II A 4; Figure 2-2]. Receptor potentials in sensory receptors (such as the pacinian corpuscle) are not action potentials and therefore do not have the stereotypical size and shape or the all-or-none feature of the action potential. Instead, they are graded potentials that vary in size depending on the stimulus intensity. A hyperpolarizing receptor potential would take the membrane potential away from threshold and decrease the likelihood of action potential occurrence. A depolarizing receptor potential would bring the membrane potential toward threshold and increase the likelihood of action potential occurrence.

49. The answer is C [Chapter 4 VII C; Table 4-5]. In a person who is standing, both ventilation and perfusion are greater at the base of the lung than at the apex. However, because the regional differences for perfusion are greater than those for ventilation, the ventilation/perfusion (V/Q) ratio is higher at the apex than at the base. The pulmonary capillary PO2 therefore is higher at the apex than at the base because the higher V/Q ratio makes gas exchange more efficient.

50. The answer is E [Chapter 5 VII D 4]. A negative value for free-water clearance (CH2O)

means that “free water” (generated in the diluting segments of the thick ascending limb and early distal tubule) is reabsorbed by the collecting ducts. A negative CH2O is consistent with high circulating levels of antidiuretic hormone (ADH). Because ADH levels are high at a time when the serum is very dilute, ADH has been secreted “inappropriately” by the lung tumor.

51. The answer is A [Chapter 5 VII C; Table 5-6]. End-organ resistance to antidiuretic hormone (ADH) is called nephrogenic diabetes insipidus. It may be caused by lithium intoxication (which inhibits the Gs protein in collecting duct cells) or by hypercalcemia (which inhibits adenylate cyclase). The result is inability to concentrate the urine, polyuria, and increased serum osmolarity (resulting from the loss of free water in the urine).

52. The answer is B [Chapter 5 IV C 3 a; VI C 2; Table 5-11]. Thiazide diuretics act on the early

distal tubule (cortical diluting segment) to inhibit Na+ reabsorption. At the same site, they enhance Ca2+ reabsorption so that urinary excretion of Na+ is increased while urinary excretion of Ca2+ is decreased. K+ excretion is increased because the flow rate is increased at the site of distal tubular K+ secretion.

53. The answer is C [Chapter 5 IX D 3; Table 5-9]. The blood values are consistent with respiratory acidosis with renal compensation. The renal compensation involves increased reabsorption of HCO3− (associated with increased H+ secretion), which raises the serum [HCO3−].

54. The answer is B [Chapter 3 VII C]. The driving force is calculated from the Starling forces across the capillary wall. The net pressure = (Pc − Pi) − (πc − πi). Therefore, net pressure = (32 mm Hg − 2 mm Hg) − (27 mm Hg) = +3 mm Hg. Because the sign of the net pressure is positive, filtration is favored.

55. The answer is B [Chapter 5 III D]. Glucose has the lowest renal clearance of the substances listed, because at normal blood concentrations, it is filtered and completely


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Board Review Series: Physiology reabsorbed. Na+ is also extensively reabsorbed, and only a fraction of the filtered Na+ is excreted. K+ is reabsorbed, but also secreted. Creatinine, once filtered, is not reabsorbed at all. Para-aminohippuric acid (PAH) is filtered and secreted; therefore, it has the highest renal clearance of the substances listed.

56. The answer is D [Chapter 2 I C 2 b]. Atropine blocks cholinergic muscarinic receptors. Because saliva production is increased by stimulation of the parasympathetic nervous system, atropine treatment reduces saliva production and causes dry mouth.

57. The answer is C [Chapter 5 IV C 2]. Na+–K+–2Cl− cotransport is the mechanism in the luminal membrane of the thick ascending limb cells that is inhibited by loop diuretics such as furosemide. Other loop diuretics that inhibit this transporter are bumetanide and ethacrynic acid.

58. The answer is A [Chapter 3 VII C; Table 3-2]. Constriction of arterioles causes decreased capillary hydrostatic pressure and, as a result, decreased net pressure (Starling forces) across the capillary wall; filtration is reduced, as is the tendency for edema. Venous constriction and standing cause increased capillary hydrostatic pressure and tend to cause increased filtration and edema. Nephrotic syndrome results in the excretion of plasma proteins in the urine and a decrease in the oncotic pressure of capillary blood, which also leads to increased filtration and edema. Inflammation causes local edema by dilating arterioles.

59. The answer is E [Chapter 4 IX A, B; Chapter 5 IX D]. Chronic obstructive pulmonary disease (COPD) causes hypoventilation. Strenuous exercise increases the ventilation rate to provide additional oxygen to the exercising muscle. Ascent to high altitude and anemia cause hypoxemia, which subsequently causes hyperventilation by stimulating peripheral chemoreceptors. The respiratory compensation for diabetic ketoacidosis is hyperventilation.

60. The answer is C [Chapter 5 VII C]. Lithium inhibits the G protein that couples the antidiuretic hormone (ADH) receptor to adenylate cyclase. The result is inability to concentrate the urine. Because the defect is in the target tissue for ADH (nephrogenic diabetes insipidus), exogenous ADH administered by nasal spray will not correct it.

61. The answer is D [Chapter 7 V A 1; Figure 7-11]. 17,20-Lyase catalyzes the conversion of glucocorticoids to the androgenic compounds dehydroepiandrosterone and androstenedione. These androgenic compounds are the precursors of testosterone in both the adrenal cortex and the testicular Leydig cells.

62. The answer is F [Chapter 5 IX D 2; Table 5-9]. The blood values and history of vomiting are consistent with metabolic alkalosis. Hypoventilation is the respiratory compensation for metabolic alkalosis. Hypokalemia results from the loss of gastric K+ and from hyperaldosteronism (resulting in increased renal K+ secretion) secondary to volume contraction.

63. The answer is B [Chapter 6 II B 1; Chapter 7 III B 3 a (1), VI D]. The actions of somatostatin are diverse. It is secreted by the hypothalamus to inhibit the secretion of growth hormone by the anterior lobe of the pituitary. It is secreted by cells of the gastrointestinal (GI) tract to inhibit the secretion of the GI hormones. It is also secreted by the delta cells of the endocrine pancreas and, via paracrine mechanisms, inhibits the secretion of insulin and glucagon by the beta cells and alpha cells, respectively. Prolactin secretion is inhibited by a different hypothalamic hormone, dopamine.

64. The answer is A [Chapter 7 IX A; Figure 7-16]. Testosterone is converted to a more active form (dihydrotestosterone) in some target tissues. Triiodothyronine (T3) is the active form of thyroid hormone; reverse triiodothyronine (rT3) is an inactive alternative form of T3. Angiotensin I is converted to its active form, angiotensin II, by the action of angiotensinconverting enzyme (ACE). Aldosterone is unchanged after it is secreted by the zona glomerulosa of the adrenal cortex.

65. The answer is E [Chapter 7 X F 2; Figure 7-20]. During the first trimester of pregnancy, the placenta produces human chorionic gonadotropin (HCG), which stimulates estrogen and



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progesterone production by the corpus luteum. Peak levels of HCG occur at about the ninth gestational week, and then decline. At the time of the decline in HCG, the placenta assumes the responsibility for steroidogenesis for the remainder of the pregnancy.

66. The answer is E [Chapter 3 V; Figure 3-15]. The atria depolarize during the P wave and then repolarize. The ventricles depolarize during the QRS complex and then repolarize during the T wave. Thus, both the atria and the ventricles are fully repolarized at the completion of the T wave.

67. The answer is C [Chapter 3 V; Figure 3-15]. Aortic pressure is lowest just before the ventricles contract.

68. The answer is A [Chapter 5 III C]. Para-aminohippuric acid (PAH) is filtered across the glomerular capillaries and then secreted by the cells of the late proximal tubule. The sum of filtration plus secretion of PAH equals its excretion rate. Therefore, the smallest amount of PAH present in tubular fluid is found in the glomerular filtrate before the site of secretion.

69. The answer is E [Chapter 5 III C; IV A 2]. Creatinine is a glomerular marker with characteristics similar to inulin. The creatinine concentration in tubular fluid is an indicator of water reabsorption along the nephron. The creatinine concentration increases as water is reabsorbed. In a person who is deprived of water (antidiuresis), water is reabsorbed throughout the nephron, including the collecting ducts, and the creatinine concentration is greatest in the final urine.

70. The answer is A [Chapter 5 IX C 1 a]. HCO3− is filtered and then extensively reabsorbed in

the early proximal tubule. Because this reabsorption exceeds that for H2O, the [HCO3−] of proximal tubular fluid decreases. Therefore, the highest concentration of [HCO3−] is found in the glomerular filtrate.

71. The answer is E [Chapter 5 V B]. K+ is filtered and then reabsorbed in the proximal tubule

and loop of Henle. In a person on a diet that is very low in K+, the distal tubule continues to reabsorb K+ so that the amount of K+ present in tubular fluid is lowest in the final urine. If the person were on a high-K+ diet, then K+ would be secreted, not reabsorbed, in the distal tubule.

72. The answer is A [Chapter 5 II C 4 b]. In the glomerular filtrate, tubular fluid closely resembles plasma; there, its composition is virtually identical to that of plasma, except that it does not contain plasma proteins. These proteins cannot pass across the glomerular capillary because of their molecular size. Once the tubular fluid leaves Bowman’s space, it is extensively modified by the cells lining the tubule.

73. The answer is B [Chapter 5 IV C 1]. The proximal tubule reabsorbs about two-thirds of the glomerular filtrate isosmotically. Therefore, one-third of the glomerular filtrate remains at the end of the proximal tubule.

74. The answer is D [Chapter 5 VII B, C]. Under conditions of either water deprivation (antidiuresis) or water loading, the thick ascending limb of the loop of Henle performs its basic function of reabsorbing salt without water (owing to the water impermeability of this segment). Thus, fluid leaving the loop of Henle is dilute with respect to plasma, even when the final urine is more concentrated than plasma.

75. The answer is C [Chapter 3 III A]. Because there are no P waves associated with the bizarre QRS complex, activation could not have begun in the sinoatrial (SA) node. If the beat had originated in the atrioventricular (AV) node, the QRS complex would have had a “normal” shape because the ventricles would activate in their normal sequence. Therefore, the beat must have originated in the His-Purkinje system, and the bizarre shape of the QRS complex reflects an improper activation sequence of the ventricles. Ventricular muscle does not have pacemaker properties.

76. The answer is B [Chapter 3 III E; VI B]. V1 agonists simulate the vasoconstrictor effects of antidiuretic hormone (ADH). Because saralasin is an angiotensin-converting enzyme


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Board Review Series: Physiology (ACE) inhibitor, it blocks the production of the vasoconstrictor substance angiotensin II. Spironolactone, an aldosterone antagonist, blocks the effects of aldosterone to increase distal tubule Na+ reabsorption, and consequently reduces extracellular fluid (ECF) volume and blood pressure. Phenoxybenzamine, an α-blocking agent, inhibits the vasoconstrictor effect of α-adrenergic stimulation. Acetylcholine (ACh), via production of endothelium-derived relaxing factor (EDRF), causes vasodilation of vascular smooth muscle and reduces blood pressure.

77. The answer is D [Chapter 3 II E]. A decrease in the capacitance of the artery means that for a given volume of blood in the artery, the pressure will be increased. Thus, for a given stroke volume ejected into the artery, both the systolic pressure and pulse pressure will be greater.

78. The answer is B [Chapter 3 IX B; Table 3-5]. During moderate exercise, sympathetic outflow to the heart and blood vessels is increased. The sympathetic effects on the heart cause increased heart rate and contractility, and the increased contractility results in increased stroke volume. Pulse pressure increases as a result of the increased stroke volume. Venous return also increases because of muscular activity; this increased venous return further contributes to increased stroke volume by the Frank-Starling mechanism. Total peripheral resistance (TPR) might be expected to increase because of sympathetic stimulation of the blood vessels. However, the buildup of local metabolites in the exercising muscle causes local vasodilation, which overrides the sympathetic vasoconstrictor effect, thus decreasing TPR. Arterial PO2 does not decrease during moderate exercise, although O2 consumption increases.

79. The answer is B [Chapter 3 VI B]. Patients with essential hypertension have decreased renin secretion as a result of increased renal perfusion pressure. Patients with congestive heart failure and hemorrhagic shock have increased renin secretion because of reduced intravascular volume, which results in decreased renal perfusion pressure. Patients with aortic constriction above the renal arteries are hypertensive because decreased renal perfusion pressure causes increased renin secretion, followed by increased secretion of angiotensin II and aldosterone.

80. The answer is E [Chapter 7 IX A]. 5α-Reductase catalyzes the conversion of testosterone to dihydrotestosterone. Dihydrotestosterone is the active androgen in several male accessory sex tissues (e.g., prostate).

81. The answer is B [Chapter 3 V; Figure 3-15]. Because the ventricles are contracting during isovolumetric contraction, ventricular pressure increases. Because all of the valves are closed, the contraction is isovolumetric. No blood is ejected into the aorta until ventricular pressure increases enough to open the aortic valve.

82. The answer is D [Chapter 4 I A, B]. Residual volume is the volume present in the lungs after maximal expiration, or expiration of the vital capacity (VC). Therefore, residual volume is not included in the tidal volume (TV), VC, inspiratory reserve volume (IRV), or inspiratory capacity (IC). The functional residual capacity (FRC) is the volume remaining in the lungs after expiration of a normal TV and, therefore, includes the residual volume.

83. The answer is E [Chapter 5 IX D 1; Table 5-9]. The blood values are consistent with metabolic acidosis (calculate pH = 7.34). Treatment with a carbonic anhydrase inhibitor causes metabolic acidosis because it increases HCO3− excretion.

84. The answer is A [Chapter 7 III B 4 a, c (2)]. Prolactin secretion by the anterior pituitary is tonically inhibited by dopamine secreted by the hypothalamus. If this inhibition is disrupted (e.g., by interruption of the hypothalamic–pituitary tract), then prolactin secretion will be increased, causing galactorrhea. The dopamine agonist bromocriptine simulates the tonic inhibition by dopamine and inhibits prolactin secretion.

85. The answer is D [Chapter 5 VII A 1; Table 5-6; Figure 5-14]. The description is of a normal person who is deprived of water. Serum osmolarity is slightly higher than normal because insensible water loss is not being replaced by drinking water. The increase in serum



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osmolarity stimulates (via osmoreceptors in the anterior hypothalamus) the release of antidiuretic hormone (ADH) from the posterior pituitary. ADH then circulates to the kidney and stimulates water reabsorption from the collecting ducts to concentrate the urine.

86. The answer is D [Chapter 3 VIII C–F; Table 3-3]. Both the pulmonary and coronary circulations are regulated by PO2. However, the critical difference is that hypoxia causes vasodilation in the coronary circulation and vasoconstriction in the pulmonary circulation. The cerebral and muscle circulations are regulated primarily by local metabolites, and the skin circulation is regulated primarily by sympathetic innervation (for temperature regulation).

87. The answer is A [Chapter 5 IX C 1; Tables 5-9 and 5-11]. Acetazolamide, a carbonic anhydrase inhibitor, is used to treat respiratory alkalosis caused by ascent to high altitude. It acts on the renal proximal tubule to inhibit the reabsorption of filtered HCO3− so that the person excretes alkaline urine and develops mild metabolic acidosis.

88. The answer is B [Chapter 5 IX D 1; Table 5-9]. The blood values are consistent with metabolic acidosis with respiratory compensation. Because the urinary excretion of NH4+ is decreased, chronic renal failure is a likely cause.

89. The answer is D [Chapter 3 VI D]. In a person with a left-to-right cardiac shunt, arterial blood from the left ventricle is mixed with venous blood in the right ventricle. Therefore, PO2 in pulmonary arterial blood is higher than normal, but systemic arterial blood would be expected to have a normal PO2 value, or 100 mm Hg. During an asthmatic attack, PO2 is reduced because of increased resistance to airflow. At high altitude, arterial PO2 is reduced because the inspired air has reduced PO2. Persons with a right-to-left cardiac shunt have decreased arterial PO2 because blood is shunted from the right ventricle to the left ventricle without being oxygenated or “arterialized.” In pulmonary fibrosis, the diffusion of O2 across the alveolar membrane is decreased.

90. The answer is D [Chapter 1 II]. H+–K+ transport occurs via H+,K+-adenosine triphosphatase (ATPase) in the luminal membrane of gastric parietal cells, a primary active transport process that is energized directly by ATP. Na+–glucose and Na+–alanine transport are examples of cotransport (symport) that are secondary active transport processes and do not use ATP directly. Glucose uptake into muscle cells occurs via facilitated diffusion. Na+–Ca2+ exchange is an example of countertransport (antiport) and is a secondary active transport process.

91. The answer is B [Chapter 6 II A 1 c; IV B 4 a]. When the pH of the stomach contents is very low, secretion of gastrin by the G cells of the gastric antrum is inhibited. When gastrin secretion is inhibited, further gastric HCl secretion by the parietal cells is also inhibited. Pancreatic secretion is stimulated by low pH of the duodenal contents.

92. The answer is A [Chapter 6 II A 2 a]. Removal of the duodenum would remove the source of the gastrointestinal (GI) hormones, cholecystokinin (CCK), and secretin. Because CCK stimulates contraction of the gallbladder (and, therefore, ejection of bile acids into the intestine), lipid absorption would be impaired. CCK also inhibits gastric emptying, so removing the duodenum should accelerate gastric emptying (or decrease gastric emptying time).

93. The answer is A [Chapter 7 III C 1 b]. Antidiuretic hormone (ADH) not only produces increased water reabsorption in the renal collecting ducts (V2 receptors), but also causes constriction of vascular smooth muscle (V1 receptors).

94. The answer is B [Chapter 6 V A 2 b]. Monosaccharides (glucose, galactose, and fructose) are the absorbable forms of carbohydrates. Glucose and galactose are absorbed by Na+-dependent cotransport; fructose is absorbed by facilitated diffusion. Dipeptides and water-soluble vitamins are absorbed by cotransport in the duodenum, and bile acids are absorbed by Na+-dependent cotransport in the ileum (which recycles them to the liver). Cholesterol is absorbed from micelles by simple diffusion across the intestinal cell membrane.


286


95. The answer is E [Chapter 7 III B 3 a (1)]. Somatostatin is secreted by the hypothalamus and inhibits the secretion of growth hormone by the anterior pituitary. Notably, much of the feedback inhibition of growth hormone secretion occurs by stimulating the secretion of somatostatin (an inhibitory hormone). Both growth hormone and somatomedins stimulate the secretion of somatostatin by the hypothalamus.

96. The answer is B [Chapter 7 X A]. Aromatase catalyzes the conversion of testosterone to estradiol in the ovarian granulosa cells. Estradiol is required for the development of female secondary sex characteristics.

97. The answer is E [Chapter 3 V; Figure 3-15]. Closure of the aortic and pulmonic valves creates the second heart sound. The closure of these valves corresponds to the end of ventricular ejection and the beginning of ventricular relaxation.

98. The answer is C [Chapter 2 II C 4; Figure 2-5]. Light striking a photoreceptor cell causes the conversion of 11-cis rhodopsin to all-trans rhodopsin; activation of a G protein called transducin; activation of phosphodiesterase, which catalyzes the conversion of cyclic guanosine monophosphate (cGMP) to 5´-GMP so that cGMP levels decrease; closure of Na+ channels by the decreased cGMP levels; hyperpolarization of the photoreceptor; and release of an excitatory or inhibitory neurotransmitter.

99. The answer is D [Chapter 7 IV A 4]. The coupling of two molecules of diiodotyrosine (DIT) results in the formation of thyroxine (T4). The coupling of DIT to monoiodotyrosine (MIT) produces triiodothyronine (T3).

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Index

Note: Page numbers in italics denote figures; those followed by “t” denote tables; those followed by “Q” denote questions; and those followed by “E” denote explanations.

A A band, 16, 17 a wave, 83 A–a (alveolar-arterial) gradient, 127–128, 128t, 139Q, 143E A-alpha nerve fibers, 36t Abdominal muscles, in expiration, 116 A-beta nerve fibers, 36t Abetalipoproteinemia, 212 Absolute refractory period (ARP), 10, 11, 24Q, 28E cardiac, 72, 73 Absorption, 90, 91 of bile acid, 208, 209, 210t of calcium, 210t, 214 of carbohydrates, 210, 210–211, 210t of electrolytes, 213–214 of iron, 210t, 214 of K⫹, 213 of lipids, 210t, 212 of NaCl, 213 of proteins, 210t, 211, 211–212 in small intestine, 197–198 of vitamins, 210t, 214 of water, 213 Accesory muscles, in breathing, 115 Accommodation, 11 ACE (angiotensin-converting enzyme) in arterial pressure regulation, 87 in regulation of angiotensin II production, 87, 88, 239 ACE (angiotensin-converting enzyme) inhibitors, 87 and renal blood flow, 149 Acetazolamide, 274Q, 285E Acetylcholine (ACh) and atrial contractility, 76 in autonomic nervous system, 31, 32, 32t, 34t and blood pressure, 284E in gallbladder contraction, 209 in gastric H⫹ secretion, 204, 204 at neuromuscular junction, 12, 12–13, 25Q, 29E in pancreatic secretion, 208 Acetylcholinesterase (AChE), 13, 14 Acetylcholinesterase (AChE) inhibitors, 13, 14, 24Q, 28E Acetylcholinesterase (AChE) receptors, in myasthenia gravis, 14, 24Q, 28E ACh (see Acetylcholine [ACh]) Achalasia, 197 Acid(s) nonvolatile, 169 production of, 168–169

titratable, 169 H⫹ excretion as, 172, 172 volatile, 168–169 weak, 155 Acid-base balance, 168–177 acid production, 168–169 buffers, 169–170, 171 and K⫹ secretion, 162 renal, 170–173, 171–172, 173 Acid–base disorder(s), 173–177, 173t causes of, 174t compensatory responses to, 173, 176t metabolic acidosis as, 173–174 metabolic alkalosis as, 174–175 respiratory acidosis as, 175–176 respiratory alkalosis as, 176–177 Acid–base map, 175 Acidemia, 173 Acidic urine pH, 155 Acidosis due to diabetes mellitus, 245 and K⫹ secretion, 162 lactic, 135 metabolic, 173–174, 173t respiratory compensation for, 173, 176t hyperchloremic, 174 causes of, 174t acid–base map of, 175 due to hypoaldosteronism, 178 due to diarrhea, 178–179, 182Q, 185E due to chronic renal failure, 183Q, 188E due to diabetes mellitus, 183Q, 188E due to diarrhea, 266Q–267Q, 278E due to carbonic anhydrase inhibitor, 273Q, 284E due to chronic renal failure, 274Q, 285E respiratory compensation for, 274Q, 285E respiratory, 173t, 175–176 causes of, 174t acid–base map of, 175 renal compensation for, 176, 176t due to COPD, 183Q, 188E renal compensation for, 270Q, 281E Acromegaly, 230 ACTH (adrenocorticotropic hormone) actions of, 223t in adrenal hormone synthesis, 237, 259Q, 262E, 263E deficiency of, 240–241 excess, 241, 258Q, 259Q, 262E, 263E in regulation of adrenocortical hormones secretion, 238, 238 in regulation of aldosterone secretion, 239 synthesis of, 228, 228, 258Q, 262E

287

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288

Index

Actin, 17 in excitation–contraction coupling, 18, 18 Action potential(s), 9–12, 10, 12, 22t cardiac, 70, 70–72, 71, 76, 269Q, 280E characteristics of, 10 conduction velocity of, 11, 12, 25Q, 28E defined, 10–11 depolarization of, 10 ionic basis of, 10, 10–11 overshoot of, 11 plateau phase of, 71, 269Q, 280E propagation of, 11, 12 refractory periods of, 10, 11 repolarization of, 11, 25Q, 28E in skeletal muscle, 18, 19 undershoot of, 11 upstroke of, 10–11, 23Q, 25Q, 27E, 28E, 72, 103Q, 110E Activation gate, of Na⫹ channel, 7 Active hyperemia, 93 Active tension, 19–20, 20 Active transport primary, 2t, 3–4, 26Q, 30E, 274Q, 285E secondary, 2t, 4, 4–5, 5, 26Q, 30E Acute respiratory acidosis, 176 Addison’s disease, 240, 240t, 241, 258Q, 259Q, 262E A-delta nerve fibers, 36t Adenoma, parathyroid, 247 Adenosine, and coronary circulation, 94 Adenosine diphosphate (ADP), in excitation– contraction coupling, 18, 19 Adenosine triphosphate (ATP) in active transport, 3–4, 26Q, 30E in excitation–contraction coupling, 18, 19 and rigor, 19, 26Q, 30E Adenylate cyclase, 224, 225, 225 norepinephrine and, 58Q, 62E parathyroid hormone and, 183Q, 188E ADP (adenosine diphosphate), in excitation– contraction coupling, 18, 19 Adrenal cortex pathophysiology of, 240–242, 240t physiology of, 235–240, 236–238 synthetic pathways in, 237 Adrenal cortical tumors, 239 Adrenal crisis, 240 Adrenal medulla, 31, 32 in hemorrhage, 99 Adrenergic receptors, 33, 33t ␣1, 33, 33t, 58Q, 62E drugs that act on, 34t, 57Q, 61E and total peripheral resistance, 269Q, 280E ␣2, 33, 33t drugs that act on, 34t ␤1, 33, 33t, 57Q, 61E ␤2, 33, 33t drugs that act on, 34t and vasodilation, 59Q, 63E Adrenocortical excess, 240t, 241 Adrenocortical hormones actions of, 239 regulation of secretion of, 238, 238–239 synthesis of, 235, 236–237, 237 Adrenocortical insufficiency, 240–241, 240t, 258Q, 259Q, 262E water shifts between compartments due to, 147t, 148

Adrenocorticotropic hormone (ACTH) actions of, 223t in adrenal hormone synthesis, 237, 259Q, 262E, 263E deficiency of, 240–241 excess, 241, 258Q, 259Q, 262E, 263E in regulation of adrenocortical hormones secretion, 238, 238 in regulation of aldosterone secretion, 239 synthesis of, 228, 228, 258Q, 262E Adrenocorticotropic hormone (ACTH)-secreting tumors, 238 Adrenogenital syndrome, 241 Adrenoreceptors, 33, 33t Afferent fibers, 190 Afterdischarge, in flexor withdrawal reflex, 50 Afterload, 19, 20, 20 ventricular, 76 and ventricular pressure–volume loops, 77, 77–79 Afterpotential, hyperpolarizing, 11 A-gamma nerve fibers, 36t Age, GFR decreases with, 150 Airflow, 118–119 Airway obstruction, (V/Q) ratio in, 131–132 Airway resistance, 119, 137Q, 141E Alanine Na⫹-dependent cotransport, 216Q, 219E in tubular fluid, 184Q, 189E Albuterol, 268Q, 279E Aldosterone actions of, 223t, 239 in colonic secretion of K⫹, 213 in hemorrhage, 99, 105Q, 112E in K⫹ secretion, 162 in Na⫹ reabsorption, 159 origin of, 235, 236, 258Q, 262E regulation of secretion of, 239, 259Q, 263E in renal acid–base balance, 172 renal effects of, 169t in renin–angiotensin–aldosterone system, 87–88, 88 in saliva production, 201 synthesis of, 237 vomiting and, 178 Aldosterone antagonist, 268Q, 280E Aldosterone synthase, 237, 269Q, 280E Aldosterone-secreting tumors, 112E, 240t, 241 Alkalemia, 174 Alkaline tide, 202 Alkaline urine pH, 155 Alkalosis contraction, 172, 175, 178 and K⫹ secretion, 162 metabolic, 173t, 174–175 due to vomiting, 174, 178, 179, 183Q, 189E causes of, 174t acid–base map of, 175 respiratory compensation for, 175, 176t, 182Q, 187E due to hyperaldosteronism, 182Q–183Q, 188E due to vomiting, 271Q, 282E respiratory, 173t, 176–177, 183Q, 188E causes of, 174t acid–base map of, 175 renal compensation for, 176–177, 176t, 182Q, 187E

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Index due to hyperventilation, 268Q, 279E in high altitudes, 274Q, 285E due to vomiting, 203 Alpha cells, 242, 243t Alpha waves, 54 ␣1 receptor(s), 33, 33t, 58Q, 62E drugs that act on, 34t, 57Q, 61E and total peripheral resistance, 269Q, 280E and vasoconstriction, 95, 103Q, 110E ␣1 receptor agonists, 34t ␣1 receptor antagonists, 34t, 57Q, 61E ␣2 receptor(s), 33, 33t drugs that act an, 34t ␣-amylases, 209 ␣-motoneurons, 47, 48 convergence on, 50 divergence to, 50 in stretch reflex, 49, 49 Altitude and hemoglobin-O2 dissociation curve, 138Q, 142E respiratory effects of, 134–135, 135t Alveolar gas equation, 128 Alveolar pressure, 120, 120 Alveolar ventilation (V), 114, 121, 131, 142E Alveoli, surface tension of, 117–118 Amacrine cell, 39, 40 Amine hormone(s), synthesis of, 222 Amino acids absorption of, 211, 211–212 free, 211 insulin and, 245 Ammonia (NH3) synthesis, 173 Ammonoum cation (NH4⫹), H⫹ excretion as, 172, 173 Anal canal, 198 Anatomic dead space, 113 Androgen(s), adrenal, 236, 236, 237, 237, 258Q, 262E, 271Q, 282E Androgen insensitivity disorder, 252, 260Q, 264E Androgen receptors, deficiency of, 252 Androstenedione, 237, 237, 251, 253, 253, 258Q, 262E Anemia iron deficiency, 214 pernicious, 214 Angiotensin I, 87 Angiotensin II and HCO3– reabsorption, 172 in hemorrhage, 99, 268Q, 279E in regulation of aldosterone secretion, 237, 239, 269Q, 280E and renal blood flow, 149 renal effects of, 169t in renin-angiotensin-aldosterone system, 87–88, 88 Angiotensin-converting enzyme (ACE) in arterial pressure regulation, 87 in regulation of angiotensin II production, 87, 88, 239 Angiotensin-converting enzyme (ACE) inhibitors, 87 and renal blood flow, 149 Angular acceleration, 45 Anion(s), and K⫹ secretion, 162 Anion gap, serum, 173–174, 176 Anosmia, 46, 62E

289

ANP (atrial natriuretic peptide) and arterial blood pressure, 89 extracellular fluid volume expansion and, 269Q, 280E mechanism of action, 223t renal effects of, 169t ANS (see Autonomic nervous system [ANS]) Anterior pituitary gland, 227 hormones of, 227–231, 228–230, 231t, 267Q, 278E removal of, 267Q, 278E Anterolateral system, 38 Anticholinergic drugs, and saliva, 202 Antidiuretic hormone (ADH) actions of, 223t, 232 and arterial blood pressure, 89 in hemorrhage, 99 hypoaldosteronism and, 178 in Na⫹ reabsorption, 159 origin of, 231 pathophysiology, 168t regulation of secretion of, 231t renal effects of, 169t syndrome of inappropriate, 270Q, 281E water shifts between compartments due to, 147, 147t urine production in, 168, 168t vs. water deprivation, 182Q, 187E and urea reabsorption, 162 in urine production, 163–168, 164, 165, 166 disorders of, 168t in vasoconstriction, 267Q, 274Q, 278E, 285E Anti-inflammatory effects, of glucocorticoids, 239 Antimüllerian hormone, 250, 250 Antiport, 2t, 4, 5 Aortic body, chemoreceptors in hemorrhage and, 99 Aortic pressure in cardiac cycle, 68, 84, 103Q, 110E, 272Q, 283E QRS complex and, 102Q, 109E and ventricular afterload, 76 Aortic valve closure of, 85, 101Q, 107E opening of, 78, 84 Aphasia, 54 motor, 54 sensory, 54 Apneustic center, 133 Apoprotein B, failure to synthesize, 212 Aromatase, 253, 274Q, 277E, 286E Aromatization, of 18-carbon steroids, 237 ARP (absolute refractory period), 10, 11, 24Q, 28E cardiac, 72, 73 Arterial pressure, 68–69 in cardiac cycle, 68, 68 and carotid sinus baroreceptors, 102Q, 109E diarrhea and, 104Q, 111E diastolic, 68, 68 exercise and, 97t gravitational forces and, 95 hemorrhage and, 98 mean, 68, 69 set point for, 86 pulse, 68, 68 regulation of, 85–89, 86, 88 systolic, 68, 68 Arterial stenosis, 105Q, 111–112E

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290

Index

Arteriolar resistance, 102Q, 109E and arterial pressure, 102Q, 109E exercise and, 97 Arteriolar vasoconstriction in baroreceptor reflex, 87 in hemorrhage, 99 Arterioles, 64 Arteriovenous shunting, in heat loss, 55 Artery(ies), 64 Aspirin for fever, 56, 268Q, 279E overdose of, 184Q, 189E Asthma, 121, 121t airway resistance in, 119 ␤2 agonists for, 58Q, 61E, 136Q, 140E, 268Q, 279E FEV1 in, 115, 115 hypxemia due to, 136Q, 140E muscles of expiration during, 116 Astigmatism, 39 Ataxia, 52 Atelectasis, 118 ATP (adenosine triphosphate) in active transport, 3–4, 26Q, 30E in excitation–contraction coupling, 18, 19 and rigor, 19, 26Q, 30E Atrial natriuretic peptide (ANP) and arterial blood pressure, 89 extracellular fluid volume expansion and, 269Q, 280E mechanism of action, 223t renal effects of, 169t Atrial pressure, 69 Atrial systole, 270Q, 281E Atrioventricular (AV) delay, 104Q, 111E Atrioventricular (AV) node, pacemaker in, 100Q, 107E Atrioventricular (AV) valves, closure of, 83, 101Q, 108E Atrium, action potentials of, 70–71 Atropine and gastric secretion, 203, 204, 205, 206 and muscarinic receptors, 34, 34t and saliva, 202, 271Q, 282E Audition, 43, 43–44 Auditory cortex, 44 Auditory ossicles, 43 Auditory pathways, central, 44 Auditory transduction, by organ of Corti, 43, 44 Auerbach’s plexus, 190, 191 Augmentation, 14 Autonomic centers, 35 Autonomic ganglia, 31, 34 Autonomic nervous system (ANS), 31–35 autonomic centers in, 35 drugs that effect, 34t of GI tract, 190–191 neurotransmitters of, 31 organization of, 31, 34, 34t receptor types in, 33–34, 33t Autonomic nervous system (ANS) effects on heart rate and conduction velocity, 73–74, 73t of thyroid hormone, 235 on various organ systems, 35t Autoregulation, of blood flow renal, 149 AV (atrioventricular) delay, 104Q, 111E

AV (atrioventricular) node, pacemaker in, 100Q, 107E AV (atrioventricular) valves, closure of, 83, 101Q, 108E Axons myelinated, 11, 12 unmyelinated, 11, 12 B B nerve fibers, 36t “Back-diffusion,” 155 Bacterial overgrowth, 212 Baloon catheter in esophagus, 120, 120 Barbiturates, 16 Baroreceptor(s), 86 gravitational forces and, 96 hemorrhage and, 98–99 Baroreceptor reflex, 86, 86–87 due to diarrhea, 179 Basal body temperature, 254, 255, 257Q, 261E Basal ganglia, in movement control, 52–53 Basal metabolic rate (BMR), thyroid hormone and, 235 Base(s), weak, 155 Basilar membrane, of organ of Corti, 43, 44, 57Q, 61E Beta cells, 242, 243t, 244 Beta waves, 53 ␤1 receptor(s), 33, 33t, 57Q, 61E drugs that act on, 34t ␤1 receptor agonist, 34t, 58Q, 62E ␤1 receptor antagonists, 34t ␤2 receptor(s), 33, 33t, 119 drugs that act on, 34t and vasodilation, 59Q, 63E, 95 ␤2 receptor agonists, 34t, 61E for asthma, 58Q, 61E, 268Q, 279E ␤2 receptor antagonists, 34t, 58Q, 61E Biconcave lens, 39 Bile, 208, 208–209 composition of, 199t, 208 formation of, 208–209 secretion of, 199t, 208–209 Bile acids absorption of, 210t cotransport of, 209, 218Q, 221E in lipid digestion, 212 primary, 209 recirculation of, 208, 209 secondary, 209 Bile salts, 208, 208 Bilirubin metabolism, 214, 215 Bipolar cells, 39, 40 Bladder, effect of autonomic nervous system on, 35t Bleeding (see Hemorrhage) Blind spot, 39 Blood flow blood vessel radius and, 66, 100Q, 107E, 270Q, 281E direction of, 64, 65 equation for, 66 hormonal control of, 93–94 laminar versus turbulent, 67, 101Q, 107E local (intrinsic) control of, 93 pulmonary, 129–130 in different regions of lung, 129, 130

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Index distribution of, 130 gravitational forces and, 130, 136Q–137Q regulation of, 130 during exercise, 135 renal, 149, 182Q, 187E resistance and, 66, 100Q, 107E velocity of, 65–66 Blood glucose and glucagon, 243 and insulin, 243, 244 Blood pressure diastolic, 68, 68 systolic, 68, 68, 105Q, 111–112E Blood urea nitrogen (BUN), 150 Blood vessel radius and blood flow, 66, 101Q, 107E, 270Q, 281E and resistance, 66, 100Q, 107E, 268Q, 279E Blood vessel(s) autonomic effects on, 73–74, 73t pressure profile in, 67–68 Blood volume and aldosterone secretion, 239, 259Q, 263E and mean systemic pressure, 79, 80 and venous return curve, 81 Blood-brain barrier anatomy of, 54 functions of, 55 passage of substances across, 90 Blue bloaters, 121 BMR (basal metabolic rate), thyroid hormone and, 235 Body fluid(s), 144–148, 145, 145t, 146, 147t Body fluid compartments, 144, 145, 145t measuring volume of, 144–146, 145t shifts of water between, 146, 146–148, 147t Body temperature basal, 254, 255, 257Q, 261E core, 56 and hemoglobin–O2 dissociation curve, 126, 126 hypothalamic set point for, 56 Bohr effect, 126 Bombesin, 195 Bone resorption calcitonin and, 249 PTH and, 247 vitamin D and, 249 Botulinus toxin, and neuromuscular transmission, 13t Bowditch staircase, 75 Bowman’s space hydrostatic pressure (PBS), 151 Bowman’s space oncotic pressure (␲BS), 151 Bradykinin, in blood flow regulation, 94 Brain stem in autonomic nervous system, 35 in control of breathing, 132–134 in posture control, 50–51 Breathing control of, 132–134, 133t mechanics of muscles of inspiration, 115 muscles of expiration, 115–116 respiratory compliance in, 116, 116–117, 117 surface tension of alveoli and surfactant, 117–118, 118 pressure, airflow, and resistance in, 118–119 breathing cycle in, 120, 120–121 with lung diseases, 121, 121t

291

Breathing cycle, 120, 120–121 Broca’s area, 54 Bromocriptine, 231, 231t, 258Q, 261E bronchial obstruction, 138Q, 142E Bronchioles, effect of autonomic nervous system on, 35t Bronchitis, chronic, 270Q, 281E brown fat, in heat generation, 55 Bruits, 67 Brush border, 209 Buffer(s), 169–170, 171 extracellular, 169 intracellular, 170 pK of, 169 titration curves, 170, 171 urinary, 169 Buffer pair, 169, 170, 181Q, 186E BUN (blood urea nitrogen), 150 C C nerve fibers, 36t, 57Q, 61E Ca2⫹ absorption of, 210t, 214 in excitation–contraction coupling, 18–19, 19 and myocardial contractility, 75, 104Q, 112E renal regulation of, 163, 182Q, 187E in tetanus, 19, 23Q, 27E Ca2⫹ homeostasis, 245 Ca2⫹ metabolism, 245–249, 246, 246t calcitonin in, 246, 246t, 249 parathyroid hormone in, 246, 246, 247–248, 248t, 259Q, 264E vitamin D in, 246, 246t, 248, 249 Ca2⫹ pump, 4, 18 Ca2⫹ reabsorption loop diuretics and, 163 thiazide diuretics and, 163, 182Q, 187E Ca2⫹ release channels, 18 Ca2⫹-ATPase, sarcoplasmic reticulum, 19 Ca2⫹-ATPase pump, 4, 18 Ca2⫹-calmodulin complex, 225, 226 Calbindin D-28K, 214 Calcitonin, 223t, 249 in calcium regulation, 246, 246t Calmodulin, 22, 225, 226 Calsequestrin, 18 cAMP (cyclic adenosine monophosphate), 224t Capacitance, vascular, 67 and pulse pressure, 273Q, 284E Capillaries, 65, 89–91 fluid exchange across, 90, 90–91 Capillary beds, 89–90 Capillary colloidosmotic pressure, 91 Capillary hydrostatic pressure, 91 glomerular, 151 Capillary oncotic pressure, 91 glomerular, 151 Capillary walls, passage of substances across, 90, 104Q, 111E, 270Q, 281E Carbaminohemoglobin, 129 Carbohydrates absorption of, 210, 210–211, 210t digestion of, 209–210, 210t metabolism, 214 Carbon dioxide (see CO2) Carbon monoxide (CO) poisoning, hemoglobin–O2 dissociation curve, 127

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292

Index

Carbonic anhydrase in acid–base balance, 169 in CO2 transport, 129, 129 in reabsorption of filtered HCO3–, 171, 171 Carbonic anhydrase inhibitors, 157, 273Q, 284E, 285E Carboxypeptidase A, 211 Carboxypeptidase B, 211 Cardiac action potentials, 70, 70–72, 71, 76, 269Q, 280E Cardiac cycle, 83–85, 84 Cardiac electrophysiology, 69–71, 69–74, 73, 73t action potentials in, 70, 70–72, 71 autonomic effects on heart rate in, 73–74, 73t conduction velocity in, 72 autonomic effects on, 73–74, 73t electrocardiogram in, 69, 69–70 excitability in, 72–73, 73 Cardiac function curve, 79, 79, 80–82, 81 Cardiac glycosides, and myocardial contractility, 76, 76 Cardiac muscle, 74–77 comparison of, 22t contractility of, 75–76, 76 depolarization of, 69 excitation–contraction coupling of, 75 length–tension relationship in, 76–77, 77 pressure–volume loops in, 77, 77–79, 78 repolarization, 272Q, 283E repolarization of, 70 structure of, 74–75 Cardiac output equation for, 66, 82 exercise and, 96 Fick principle for measuring, 83 in Frank–Starling relationship, 77, 77 gravitational forces and, 95 hemorrhage and, 98 on left and right sides of heart, 64, 104Q, 111E myocardial contractility and, 102Q, 109E of right ventricle, 129–130 and venous return, 77 Cardiac output curve, 79, 79, 80–82, 81 negative inotropic agents and, 81, 265Q, 276E positive inotropic agents and, 81, 81 Cardiac oxygen consumption, 82 Cardiac pacemaker, 71 in AV node, 100Q, 107E latent, 71 Cardiovascular effects, of thyroid hormone, 235 Cardiovascular physiology, 64–112 arterial pressure, regulation in, 85–89, 86, 88 cardiac cycle, 83–85, 84 cardiac electrophysiology, 69–71, 69–74, 73, 73t cardiac muscle and cardiac output, 74–83, 76–81 circuitry of the cardiovascular system, 64, 65 hemodynamics in, 64–69, 65, 68 integrative functions of the cardiovascular system in, 95–99, 95t, 96–98, 97t, 98t microcirculation and lymph in, 89–92, 90, 92t of special circulations, 92–95, 92t Cardiovascular responses, to standing, 95–96, 95t, 96, 100Q, 107E Cardiovascular system circuitry of, 64, 65 exercise and, 96–97, 97, 97t gravitational forces and, 95–96, 95t, 96

Carotid body, chemoreceptors in, 89 in control of breathing, 133t, 134 hemorrhage and, 99 Carotid sinus baroreceptors gravitational forces and, 96 hemorrhage and, 99 Carotid sinus nerve, in baroreceptor reflex, 86 Carrier-mediated transport, 3 Catecholamines glucocorticoids and, 239 and myocardial contractility, 76 synthetic pathways, 15, 15 Catechol-O-methyltransferase (COMT), 15 Caudad region, of stomach, 197 Cecum, 198 Cell membranes structure of, 1 transport across, 2–5, 2t, 4, 5 Cell physiology, 1–30 of cardiac muscle, 22t cell membranes in, 1 transport across, 2–5, 2t, 4, 5 diffusion potential, resting membrane potential, and action potential in, 7–12, 8, 10, 12 neuromuscular and synaptic transmission in, 12, 12–16, 13t, 15 osmosis in, 5–7, 6 of skeletal muscle in, 16–20, 17, 18, 19, 20, 22t of smooth muscle, 20–22, 21, 22t Central auditory pathways, 44 Central diabetes insipidus, 166, 168, 168t, 181Q, 186E, 268Q, 279E Central nervous system (CNS) effects, of thyroid hormone, 235 Cerebellar cortex connections in, 52 inputs to, 52 layers of, 52 outputs of, 52 Cerebellum clinical disorders of, 52 functions of, 51 in movement control, 51–52, 59Q, 63E Cerebral circulation, regulation of, 92t, 94, 104Q, 111E Cerebral cortex, 133 in control of breathing, 133 higher functions of, 53–54 sensory pathways to, 37–38 Cerebral ischemia, and arterial blood pressure, 89, 99 Cerebrospinal fluid (CSF) composition of, 54, 55t, 58Q, 62E CFTR (cystic fibrosis transmembrane conductance regulator) gene, 208 Chemical synapses, 12 Chemoreceptor(s), 36, 37 in carotid and aortic bodies, 89 hemorrhage and, 99 in control of breathing, 134 in medulla, in control of breathing, 133–134 in vasomotor center, 89 Chemoreceptor trigger zone, for vomiting, 199 Chenodeoxycholic acid, 209 Chest wall compliance, 117, 117 Chewing, 196 Chief cells, 202, 202t, 203, 246

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Index Chlorothiazide, 182Q, 187E, 270Q, 281E CH2O(free-water clearance), 167–168, 181Q, 186E, 265Q–266Q, 276E, 281E Cholecalciferol, 249 Cholecystokinin (CCK), 192, 192t, 193 actions of, 192t, 193 in gallbladder contraction, 209 and gastric emptying, 216Q, 217Q–218Q, 219E, 220E–221E, 285E in gastric motility, 197 gastrin-like properties of, 216Q, 219E in lipid digestion, 212 and pancreatic secretion, 207, 217Q, 220E stimulus for the release of, 192t, 193 Cholera, pancreatic, 195 Cholera toxin, 213, 216Q, 219E Choleretic agents, 209 Cholesterol absorption of, 212 in adrenal hormone synthesis, 237 in synthesis of testosterone, 251 Cholesterol desmolase, 237, 238, 263E Cholic acid, 209 Choline acetyltransferase, at neuromuscular junction, 12 Cholinergic neurons, 31 Cholinergic receptors, 34, 34t Cholinoreceptors, 34, 34t Chorda tympani, lesion of, 59Q, 63E Choroid plexus epithelium, CSF formation by, 54 Chromaffin cells, 31 Chronic bronchitis, 121, 121t, 270Q, 281E Chronic obstructive pulmonary disease (COPD), 121, 121t hypoventilation due to, 271Q, 282E intrapleural pressure on, 121 respiratory acidosis due to, 183Q, 188E Chronic renal failure metabolic acidosis due to, 183Q, 188E, 274Q, 285E and PTH, 248, 248t and vitamin D, 258Q–259Q, 262E Chronic respiratory acidosis, 176 Chronotropic effects, 73, 74 Chylomicrons, 212 Chyme, 198 Chymotrypsin, 211 Cimetidine for duodenal ulcer, 217Q, 220E and gastric secretion, 204, 204, 205, 206 Circadian rhythm of glucocorticoid secretion, 238 of sleep, 54 Circular muscle, 190, 191 in gastrointestinal motility, 195 Circulation(s) cerebral, 92t, 94 coronary, 92t, 94 hormonal (extrinsic) control of, 93–94 local (intrinsic) control of, 93 pulmonary, 92t to skeletal muscle, 92t, 94–95 to skin, 95 special, 92–95, 92t Circumvallate papillae, 46 Cl–, intestinal secretion of, 213 Cl– diffusion potential, 8, 8 Cl– equilibrium potential, 8

293

Cl– shift, 129 Clasp-knife reflex, 49t, 50 Clearance equation, 148 Cl––HCO3– exchange, 202 Climbing fibers, 52 CNS (central nervous system) effects, of thyroid hormone, 235 CO (see Carbon monoxide (CO)) CO2 and cerebral circulation, 92t, 94, 104Q, 111E in control of breathing, 133, 134 diffusion limited exchange of, 123 dissolved, 128 forms of, 128–129, 129 partial pressure of, 122, 123t and hemoglobin-O2 dissociation curve, 127, 127, 128 arterial, 134, 135, 138Q–139Q venous, 135 and HCO3– reabsorption, 171 production of, 168 CO (Carbon monoxide) poisoning, hemoglobin–O2 dissociation curve, 127 CO2 diffusion, 123 CO2 transport, 128–129, 129, 266Q, 277E Cochlea, 44 Cochlear microphonic potential, 44 Collecting duct and Ca2⫹ reabsorption, 163 in K⫹ regulation, 160 Na⫹ reabsorption in, 156, 156–157 in urine production, 166, 167 Colloidosmotic pressure, 6 capillary, 91 Colon, 198 Compensatory responses to acid–base disorders, 173, 174, 175, 176–177, 176t to hemorrhage, 98–99, 98t to raise blood pressure with gravitational forces, 95–96, 95t Competition, in carrier-mediated transport, 3 Complex cells, of visual cortex, 42, 58Q, 61E Compliance chestwall, 117, 117 lung, 116, 116–117, 117 respiratory, 116, 116–117, 117 vascular, 67 COMT (catechol-O-methyltransferase), 15 Concentration gradient flux, 8, 24Q, 28E Conductance, of ion channels, 7 Conduction, saltatory, 11, 12 Conduction velocity, 11, 12, 25Q, 28E cardiac, 72 autonomic effects on, 73–74, 73t Cones, 39, 40t, 57Q, 61E Conjugated bilirubin, 214, 215 Conn’s syndrome, 183Q, 188E, 240t, 241 Contraction alkalosis, 172, 175, 178 Convection, heat loss by, 55 Convergence, 50 Convex lens, 39 COPD (Chronic obstructive pulmonary disease ), 121, 121t Core temperature, 56 Coronary circulation, regulation of, 92t, 94 Corpus luteum, 254, 255, 256, 257Q, 259Q, 261E, 263E

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294

Index

Cortical diluting segment, 159 Cortical evoked potential, 53 Corticobulbar tract, 50 Corticopapillary osmotic gradient, 163–164, 167 Corticospinal tract, 50 Corticosterone, 237, 239 Corticotropin-releasing hormone (CRH), 223t, 238, 238–239 Cortisol actions of, 223t, 239 origin of, 235 regulation of secretion of, 238–239 synthesis of, 237 Cotransport, 2t, 4, 4, 26Q, 29E Countercurrent multiplication, in loop of Henle, 164 Countertransport, 2t, 4, 5, 5 Coupled transport, 4 Creatinine, serum, 150 Creatinine concentration, in tubular fluid, 272Q, 283E CRH (corticotropin-releasing hormone), 223t, 238, 238–239 Cribriform plate, fracture of, 46, 62E Cross-bridges, 18, 19, 20, 20 Crossed extension reflex, 50 Crypts, intestinal, 213 CSF (cerebrospinal fluid) composition of, 54, 55t, 58Q, 62E pH of, in control of breathing, 123 Cupula, 45, 45 Curare, and neuromuscular transmission, 13t Current inward, 10, 269Q, 280E outward, 10 Cushing reaction, 89 Cushing’s disease, 240t, 241, 258Q, 262E Cushing’s syndrome, 240t, 241 Cyclic adenosine monophosphate (cAMP), 224t Cyclooxygenase, inhibition of, 56 Cylindric lens, 39 Cystic fibrosis, 208 Cystic fibrosis transmembrane conductance regulator (CFTR) gene, 208 D D1 receptors, 15, 53 D2 receptors, 15, 53 Dalton’s law, of partial pressures, 122 Dead space, 113–114 Decerebrate rigidity, 51, 58Q, 62E Decibels (dB), 43 Decorticate posturing, 51 Defecation, 198, 217Q, 220E Dehydroepiandrosterone, 236, 237, 237, 251, 258Q, 262E Dehydroepiandrosterone-sulfate (DHEA-S), 255, 263E Delta cells, 242, 243t Deoxycholic acid, 209 Deoxycorticosterone, 236 11-Deoxycorticosterone, 237 11-Deoxycortisol, 237 Deoxyhemoglobin, 129, 139Q, 143E as intracellular buffer, 170 Depolarization, 9, 269Q, 280E of cardiac muscle, 69 of T tubules, 18

Dermatome rule, 39 Detoxification, liver function, 215 Dexamethasone suppression test, 238–239 ␣-Dextrinase, 209 DHEA-S (Dehydroepiandrosterone-sulfate), 255, 263E Diabetes insipidus central, 166, 168, 168t, 181Q, 186E, 268Q, 279E nephrogenic, 166, 168, 168t, 270Q, 271Q, 281E, 282E urine production in, 166, 168, 168t water shifts between compartments due to, 147t Diabetes mellitus, 245, 259Q, 263E–264E metabolic acidosis due to, 183Q, 188E Diabetic ketoacidosis, 269Q, 280E Diacylglycerol, 225 Diaphragm, in breathing, 115 Diarrhea and arterial pressure, 104Q, 111E due to cholera toxin, 214, 216Q, 219E due to Escherichia coli, 214 hypokalemia due to, 213 due to lactose intolerance, 211 metabolic acidosis due to, 178–179, 266Q–267Q, 278E secretory, 214 water shifts between compartments due to, 147, 147t Diastasis, 85 Diastole, 68 Diastolic pressure, 68, 68 Diastolic pressure curve, 77 Dicrotic notch, 85, 109E Dietary K⫹, 161–162 Diffusion back, 155 facilitated, 2t, 3 measurement of, 2 nonionic, 155 sample calculation for, 2 simple, 2–3, 2t, 25Q, 29E across capillary wall, 90 Diffusion potential, 7–8, 8, 23Q, 27E Diffusion trapping, 172 Digestion of carbohydrates, 209–210, 210t of lipids, 210t, 212 of proteins, 210t, 211 in small intestine, 197–198 in stomach, 197 Digitalis and cardiac output curve, 81 and myocardial contractility, 76, 76 Dihydropyridine receptor, 18 Dihydrotestosterone, 225, 250, 251, 252, 260Q, 264E, 271Q, 282E 1,25-Dihydroxycholecalciferol, 249, 258Q–259Q, 262E actions of, 223t, 249 and calcium metabolism, 214, 246, 248, 249 regulation of synthesis of, 249, 249 24,25-Dihydroxycholecalciferol, 249 3,4-Dihydroxymandelic acid (DOMA), 15 Diiodotyrosine (DIT), 233, 233, 275Q, 286E Diluting segment, 158, 164 Dilution method, for measuring volume of fluid compartments, 144–146

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Index Diopters, 39 Dipalmitoyl phosphatidylcholine (DPPC), 118 Dipeptides, 211, 212 2,3-Diphosphoglycerate (2,3-DPG), and hemoglobin–O2 dissociation curve, 126, 126 in high altitude, 135 Disaccharides, digestion and absoption of, 217Q, 220E Dissolved gases, 122 Distal tubule and Ca2⫹ reabsorption, 163 in K⫹ regulation, 160, 180Q, 185E Na⫹ reabsorption in, 156, 156–157 in urine production, 166, 167 DIT (diiodotyrosine), 233, 233, 275Q, 286E Diuretics effects on nephron of, 177t K⫹-sparing, 159 loop site of action of, 158, 177t and K⫹ secretion, 162 and Ca2⫹ excretion, 163 isosthenuric urine due to, 168 major effects of, 177t mechanism of action of, 177t for hypercalcemia, 277E thiazide site of action of, 158, 177t and K⫹ secretion, 162 and Ca2⫹ reabsorption, 163, 182Q, 187E for idiopathic hypercalciuria, 163 major effects of, 177t mechanism of action of, 177t contraindications to, 266Q, 277E mechanism of action of, 270Q, 281E Divergence, 50 DOMA (3,4-dihydroxymandelic acid), 15 Dopamine, 14, 15, 223t in control of movement, 53 and prolactin secretion, 230, 230 synthetic pathway for, 15 Dopaminergic neurons, in Parkinson’s disease, 15, 26Q, 30E Dorsal column system, 38 Dorsal respiratory group, 133 Down-regulation of receptors, 224 2,3-DPG (2,3-diphosphoglycerate), and hemoglobin–O2 dissociation curve, 126, 126 in high altitude, 135 DPPC (dipalmitoyl phosphatidylcholine), 118 Dromotropic effects, 73 Duodenal ulcers, 206, 217Q, 220E Duodenum, surgical removal of, 274Q, 285E Dysdiadochokinesia, 52, 59Q, 63E E Ear, structure of, 43, 43–44 ECF (see Extracellular fluid [ECF]) ECG (electrocardiogram), 69–70, 70 Edema arteriolar constriction and, 271Q, 282E causes of, 91, 92t due to gravitational forces, 95 venous pressure and, 102Q, 109E EDRF (endothelium-derived relaxing factor), 92 Effective refractory period (ERP), cardiac, 72, 73 Efferent fibers, 190

295

Ejection fraction, 75, 82 and end-diastolic volume, 82, 107E and end-systolic volume, 100Q, 107E Elastase, 211 Electrical syncytium, heart as, 74 Electrocardiogram (ECG), 69–70, 70 Electrochemical equilibrium, 7, 23Q–24Q, 27E Electrochemical gradient, 2, 3, 23Q, 25Q, 27E, 29E Electroencephalographic (EEG) findings, 53–54 Electrolytes absorption of, 213–214 secretion of, 213 Embolism, pulmonary, V/Q ratio in, 132 Emmetropia, 39 Emphysema diffusion-limited exchange for, 123 lung compliance in, 117 respiratory acidosis due to, 270Q, 281E End plate potential (EPP), 13 End-diastolic volume, 76 calculation of, 106Q, 112E ejection fraction and, 82, 107E and stroke volume, 77, 77 Endocrine physiology, 222–264 of adrenal cortex, 235, 236–238, 236–242, 240t of calcium metabolism, 245–249, 246, 246t, 248t, 249 cell mechanisms and second messengers in, 224–227, 224t, 225–227 of female reproduction, 253, 253–256, 254t, 255–256 of male reproduction, 250–252, 251–252 overview of hormones in, 222–224, 223t of pancreas, 242–245, 242t–244t of pituitary gland, 227–232, 228–230, 231t of sexual differentiation, 249–250, 250 of thyroid gland, 232–235, 233–234, 236t Endolymph, 43, 44, 45 Endopeptidases, 211 ␤–Endorphin, 228, 228 Endothelium-derived relaxing factor (EDRF), 92 End-systolic volume, ejection fraction and, 100Q, 107E Enkephalins, 195 Enteric nervous system, 31, 191 Epinephrine, 14, 15 in hemorrhage, 99 synthetic pathway for, 15 and vasoconstriction, 63E and vasodilation, 59Q, 63E Epinephrine, cutaneous circulation and, 265Q, 276E Epithelial cells, of GI tract, 190, 191 EPP (end plate potential), 13 EPSPs (excitatory postsynaptic potentials), 14 Equilibrium point, for cardiovascular system, 79, 81 Equilibrium potential, 7–9, 10, 24Q, 28E ERP (effective refractory period), cardiac, 72, 73 ERV (expiratory reserve volume), 113, 114 Erythropoietin, in high altitudes, 135 Escherichia coli, diarrhea due to, 214 Esophageal motility, 196–197 Esophagus, baloon catheter in, 120, 120 Essential hypertension, plasma renin activity in, 273Q, 284E

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296

Index

Estradiol actions of, 223t in menstrual cycle, 254, 255, 257Q, 261E origin of, 223t synthesis of, 237, 266Q, 277E Estriol, 256, 256 Estrogen(s) actions of, 253, 254 during pregnancy, 255, 256, 259Q, 263E synthesis of, 253, 253 Evans blue, and plasma volume, 145 Excitability, of cardiac cells, 72–73, 73 Excitation–contraction coupling cardiac, 75 in skeletal muscle, 18, 18–19, 19 temporal sequence of, 25Q–26Q, 29E Ca2+ binding in, 266Q, 277E–278E in smooth muscle, 21, 21–22, 23Q, 27E, 266Q, 277E–278E Excitatory neurotransmitters, 12, 14 Excitatory postsynaptic potentials (EPSPs), 14 Excretion of Ca⫹, 163 of glucose, 153, 153 of H⫹, 172, 172–173, 173 of K⫹, 159–161 of Na⫹, 156–157 of PAH, 154, 154 of urea, 163 of weak acids and bases, 155 Exercise and blood flow to skeletal muscle, 95 cardiovascular effects of, 97, 97, 98t diffusion-limited gas exchange, 122–123 hyperkalemia due to, 182Q, 188E muscles of expiration during, 116 muscles of inspiration during, 115 respiratory effects of, 134–135, 135t and stroke volume, 273Q, 284E Exocytosis, 212 Exopeptidases, 211 Expiration muscles of, 115–116 volumes and pressure during, 121, 121 Expiratory reserve volume (ERV), 113, 114, 136Q, 140E External intercostals muscles, in breathing, 115 Extracellular buffers, 169 Extracellular fluid (ECF), 144, 145, 145t shifts between compartments of, 146, 146–148, 147t Extracellular fluid (ECF) volume and atrial natriuretic peptide, 269Q, 280E and HCO3– reabsorption, 172 mannitol and, 144–145, 181Q, 186E measurement of, 145–146, 145t and proximal tubular reabsorption, 158 Extrafusal fibers, 47 Extrapyramidal tracts, 50 Extrasystolic beat, 100Q, 107E Eye, effect of autonomic nervous system on, 35t F Facilitated diffusion, 2t, 3 Facilitation, 14 Farsightedness, 39 Fast pain, 39

Fat(s) absorption of, 210t, 212, 267Q, 278E digestion of, 210t, 212 malabsorption of, 210t, 212 Fat cells, effect of autonomic nervous system on, 35t Fatty acid glucagon and, 243 insulin and, 244 Fatty acid(s) absorption of, 212 Fatty acid tails, of phospholipids, 1 Fe2⫹ (ferrous iron), 123 absorption of, 210t, 214 Fe3⫹ (ferric iron), 124 Female phenotype, 250, 250, 274Q, 286E Female reproduction, 253–256 estrogen in, 253, 253, 254 menstrual cycle in, 254, 255 pregnancy in, 255–256, 256 progesterone in, 253, 253, 254 regulation of ovary in, 253, 254t Ferric iron (Fe3⫹), 124 Ferrous iron (Fe2⫹), 123 absorption of, 210t, 214 Fertilization, 255 Fetal hemoglobin and hemoglobin-O2 dissociation curve, 125, 126, 265Q, 276E Fetal lung, surfactant in, 118 Fetal pulmonary vascular resistance, 130 FEV1 (Forced expiratory volume), 115, 115 Fever, 56 due to Streptococcus pyogenes, 267Q, 279E water shifts between compartments due to, 147t Fibrosis, 121, 121t diffusion-limited exchange for, 123 FEV1 in, 115, 115 lung compliance in, 117 PaCO2 in, 138Q–139Q, 143E Fick principle, 83 Filtered load calculation of, 152 of glucose, 153, 153 of HCO3–, 171 of PAH, 154, 154 Filtration, 90, 90 factors that increase, 91 Filtration fraction, 150, 152t, 181Q, 186E Finasteride, 250 First heart sound, 83, 101Q, 108E First-order neurons, 37 Fixed acids, 169 Flexor withdrawal reflex, 49t, 50, 59Q, 63E Fluid(s), body, 144–148, 145, 145t, 146, 147t Fluid compartments, 144, 145, 145t measuring volume of, 144–146, 145t shifts of water between, 146, 146–148, 147t Fluid exchange, across capillaries, 90, 90–91, 101Q, 108E Flux, concentration gradient, 8, 24Q, 28E Foliate papillae, 46 Follicle-stimulating hormone (FSH) actions of, 223t in menstrual cycle, 254, 255 origin of, 223t in regulation of ovary, 253

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Index regulation of secretion, 251, 258Q, 261E, 265Q, 276E in regulation of testes, 251, 252 structure of, 228 variation over life span, 252 Follicular phase, of menstrual cycle, 254, 255 Forced expiratory volume (FEV1), 115, 115 Forced vital capacity (FVC), 115, 115 Force-generating stroke, 19 Force–velocity relationship, in skeletal muscle, 20, 20 Fourth heart sound, 83 Fourth-order neurons, 38 Frank–Starling relationship, 77, 77 FRC (functional residual capacity), 114, 114, 273Q, 284E Free amino acids, 211 Free nerve endings, 39, 47 Free-water clearance (CH2O), 167–168, 181Q, 186E, 265Q–266Q, 276E, 281E Frequency, of sound, 43, 44 Fructose, absorption of, 210, 210–211, 274Q, 285E Functional residual capacity (FRC), 114, 114, 273Q, 284E Fungiform papillae, 46 Furosemide, 158, 158, 163, 271Q, 282E FVC (forced vital capacity), 115, 115 G G cells, 193, 202, 202t, 203 GABA (␥–aminobutyric acid), 14, 16, 26Q, 29E, 52 Galactorrhea, 231, 258Q, 261E Galactose, absorption of, 210, 210 Gallbladder, 208, 208–209 contraction of, 209 ␥-aminobutyric acid (GABA), 14, 16, 26Q, 29E, 52 ␥-motoneurons, 47, 48 in stretch reflex, 49 Ganglion cells, 39, 40, 41 receptive fields of, 41–42 Ganglionic blockers, 34, 57Q, 61E Gap junctions, 1 myocardial, 74 Gas(es) diffusion of, 122 dissolved, 122 Gas exchange, 122–123 Gastrectomy, and vitamin B12, 210t, 214 Gastric emptying, 197 cholecystokinin and, 216Q, 217Q–218Q, 219E, 220E–221E removal of duodenum and, 274Q, 285E Gastric motility, 197 Gastric parietal cells, 193 Gastric secretion, 199t, 202–206 cells in, 202, 202t, 203 inhibition of, 199t, 204, 205 mechanism of, 202–203, 203 and peptic ulcer disease, 205–206 products of, 199t, 202t stimulation of, 199t, 202t, 203–205, 204 Gastric ulcers, 205 Gastrin, 192–193, 192t, 202, 202t, 203 actions of, 192t, 193 and gastric secretion, 204, 204, 205 secretion of, 193 stimulus for, 192t, 193, 202t, 203

297

inhibition of, 193, 216Q, 219E in Zollinger–Ellison syndrome, 193 site of, 202, 202t, 203, 216Q–217Q, 219E hyper-, 212 inhibition of, 274Q, 285E types of, 192 Gastrinoma, 193, 218Q, 221E Gastrin-releasing peptide (GRP), 193, 194, 195 Gastrin-secreting tumors, 193 Gastrocolic reflex, 198–199 Gastroesophageal reflux, 196 Gastroileal reflex, 198 Gastrointestinal (GI) hormones, 191–194, 192, 192t Gastrointestinal (GI) motility, 195, 195–199 Gastrointestinal (GI) secretion, 199–209, 199t of bile, 199t, 208–209 gastric, 199t, 202–206, 202t, 203, 204 salivary, 199–202, 199t, 200, 201 Gastrointestinal (GI) tract, 190–221 digestion and absorption in, 209–214, 210, 210t of carbohydrates, 209–211, 210, 210t of bile acids, 210t of calcium, 210t, 214 of iron, 210t, 214 of lipids, 210t, 212 of proteins, 210t, 211, 211–212 of vitamins, 210t, 214 of water, 213 of electrolytes, 213–214 effect of autonomic nervous system on, 35t innervation of, 190–191 liver physiology, 214–215, 215 regulatory substances in, 191–195, 192, 192t structure of, 190, 191 Generator potential, 37, 37 Genetic sex, 249 Geniculocalcarine tract, 40 lesion of, 40, 41 GFR (see Glomerular filtration rate [GFR]) GH (see Growth hormone [GH]) GI (see Gastrointestinal [GI]) Gigantism, 230 GIP (glucose-dependent insulinotropic peptide), 192, 192t, 194, 217Q, 220E Globus pallidus, 52, 53 Glomerular capillaries, in K⫹ regulation, 159 Glomerular capillary hydrostatic pressure (PGC), 151 Glomerular capillary oncotic pressure (␲GC), 151, 180Q, 185E Glomerular filtrate, in tubular fluid, 272Q, 283E Glomerular filtration rate (GFR), 150–152 blood urea nitrogen and, 150 filtration fraction and, 150 increase in, 181Q, 186E–187E, 267Q, 278E inulin clearance and, 150, 180Q, 185E serum creatinine and, 150 Starling forces in, 150–151, 151, 152t Glomerular markers, 155 Glomerulotubular balance, in proximal tubule, 156, 157–158, 158 Glucagon, 223t, 242t, 243, 243t Glucocorticoids actions of, 223t, 239 origin of, 235, 236, 237 regulation of secretion of, 238, 238–239

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298

Index

Gluconeogenesis glucagon and, 243 glucocorticoid stimulation of, 239 insulin and, 244 Glucose absorption of, 210, 210 blood and glucagon, 243 and insulin, 243, 244 excretion of, 153, 153, 181Q, 186E filtered load of, 153, 153 reabsorption of, 153, 153, 267Q, 278E renal clearance of, 271Q, 281E–282E transport maximum (Tm) curve for, 153, 153–154 in tubular fluid, 184Q, 189E Glucose titration curve, 153, 153–154 Glucose transporter 2 (GLUT 2), 210 Glucose transporter 2 (GLUT 2) receptor, 244 Glucose-dependent insulinotropic peptide (GIP), 192, 192t, 194 Glutamate, 14, 16 Glycerol, absorption of, 212 Glycerol backbone, of phospholipids, 1 Glycine, 14, 16 Glycogen, insulin and, 244 Glycogenolysis glucagon and, 243 insulin and, 244 Golgi tendon organs, 47 Golgi tendon reflex, 49–50, 49t Gonadal sex, 249 Gonadotropin-releasing hormone (GnRH) actions of, 223t mechanism of action, 259Q, 263E in puberty, 252 in regulation of ovary, 253 in regulation of testes, 251, 252 Granular layer, of cerebellar cortex, 52 Granulosa cells, 253 Graves’ disease, 234, 259Q, 262E–263E Gravitational forces and cardiovascular system, 95–96, 95t, 96 and pulmonary blood flow, 130, 136Q–137Q, 141E Growth, thyroid hormone and, 234–235 Growth hormone (GH), 223t, 228, 229–230, 258Q, 262E regulation of secretion, 274Q, 286E regulation of secretion of, 228, 229, 229 Growth hormone (GH) deficiency, 230 Growth hormone (GH) excess, 230 Growth hormone-releasing hormone (GHRH), 223t, 229, 229 GRP (gastrin-releasing peptide), 193, 194, 195 Guanosine triphosphate (GTP)-binding (G) proteins, 224 H H⫹ in control of breathing, 133, 134 excretion of, 172, 172–173, 173, 181Q, 185E H band, 17 H⫹ secretion, 202–206 cells in, 202, 202t, 203 inhibition of, 199t, 204, 205 mechanism of, 202–203, 203 and peptic ulcer disease, 205–206 stimulation of, 199t, 202t, 203–205, 204

H2 receptors, 204, 204 H2 receptor blockers, 204, 205 Hair cells, 45, 45, 59Q, 63E H⫹-ATPase, 172 Haustra, 198 HbF (hemoglobin F) and hemoglobin-O2 dissociation curve, 125–127, 265Q, 276E HCG (human chorionic gonadotropin), 223t, 255, 271Q, 282E–283E HCO3– in CO2 transport, 129 as extracellular buffer, 169 and gastric acid secretion, 202–203, 203 and K⫹ secretion, 162 in metabolic acidosis, 173 in metabolic alkalosis, 175 in pancreatic secretion, 206, 207 reabsorption of filtered, 170–173, 171–172, 173 in saliva, 266Q, 277E in tubular fluid, 272Q, 283E H⫹-dependent cotransport, of dipeptides and tripeptides, 212 Heart, effect of autonomic nervous system on, 35t Heart rate autonomic effects on, 73–74, 73t in baroreceptor reflex, 87 ␤1 receptors and, 33, 57–58Q, 61E, 105Q, 112E and ventricular filling, 268Q, 279E Heart size, and myocardial O2 consumption, 104Q, 111E Heart sound(s), 83, 84, 85 first, 83, 101Q, 108E fourth, 83 second, 85, 102Q, 109E, 275Q, 286E Heartburn, 196 Heat exhaustion, 56 Heat stroke, 56 Heat-generating mechanisms, 55, 56 Heat-loss mechanisms, 55, 56 Helicobacter pylori, 205 Heme moiety, 123 Hemicholinium, and neuromuscular transmission, 13, 13t Hemodynamics, 64–69, 65, 68 arterial pressure in, 68, 68–69 atrial pressure in, 69 capacitance (compliance) in, 67 components of vasculature in, 64–65 equation for blood flow, 66 pressure profile in blood vessels in, 67–68 resistance in, 66–67 velocity of blood flow in, 65–66 venous pressure in, 69 Hemoglobin, 123–124 as intracellular buffer, 170 O2 transport in, 123–124 Hemoglobin F (hBF) and hemoglobin-O2 dissociation curve, 125–127, 265Q, 276E Hemoglobin S, 124 Hemoglobin-O2 dissociation curve, 124–125 altitude and, 138Q–139Q, 142E–143E changes in, 125–127, 126, 127 exercise and, 126, 137Q, 141E fetal hemoglobin and, 125, 126, 265Q, 276E P50 and, 125, 126, 137Q, 141E, 265Q, 276E

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Index Hemorrhage, 130 baroreceptor reflex in, 86 cardiovascular responses to, 98, 98–99, 98t, 268Q, 279E renin–angiotensin–aldosterone system in, 88, 99, 105Q, 112E Henderson–Hasselbalch equation, 170, 186E Hepatic failure, and thyroid hormones, 234 Hering–Breuer reflex, 134 Hering’s nerve, in baroreceptor reflex, 86 Hertz (Hz), 43 hexamethonium, 34, 57Q, 61E High-K⫹ diet, 161 Hippocampus, in memory, 54 Hirschsprung’s disease, 199 Histamine, 16, 194 in blood flow regulation, 94, 95, 104Q, 110E gastric secretion of, 204, 204, 205 glucocorticoids and, 239 H⫹-K⫹ pump, 4, 202 H⫹–K⫹ transport, 274Q, 285E H⫹,K⫹-ATPase, 4, 160, 202 Horizontal cells, 39, 40 Hormone(s) mechanisms of action of, 224–227, 224t, 225–227 overview of, 222–224, 223t regulation of secretion of, 222 synthesis of, 222 Hormone receptors, regulation of, 224 Hormone-receptor dimers, 227, 227 HPL (human placental lactogen), 223t, 256, 256 Human chorionic gonadotropin (HCG), 223t, 255, 271Q, 282E–283E Human placental lactogen (HPL), 223t, 256, 256 Humoral hypercalcemia of malignancy, 247, 248t, 266Q, 277E Huntington’s disease, 53 Hydrochloric acid (HCl) secretion, 202–206 activation of pepsinogen by, 267Q, 278E cells in, 202, 202t, 203 inhibition of, 199t, 204, 205 mechanism of, 202–203, 203 and peptic ulcer disease, 205–206 stimulation of, 199t, 202t, 203–205, 204 Hydrogen ion (see H⫹) 17-Hydropregnenolone, 258Q, 262E Hydrostatic pressure Bowman’s space, 151 capillary, 90–91 glomerular, 151 interstitial fluid, 91 25-Hydroxycholecalciferol, 249, 258Q–259Q, 262E 1␣-Hydroxylase, 249, 262E 11␤-Hydroxylase, 237 17␣-Hydroxylase, 237 17␣-Hydroxylase deficiency, 240t, 242 21␤-Hydroxylase, 237 21␤-Hydroxylase deficiency, 240t, 241–242 17-Hydroxypregnenolone, 237, 242, 251, 258Q, 262E 17-Hydroxyprogesterone, 237 3␤-Hydroxysteroid dehydrogenase, 237 17␤-Hydroxysteroid dehydrogenase, 253 5-hydroxytryptamine, in blood flow regulation, 94 Hyperaldosteronism, 240t, 241 hypertension due to, 183Q, 188E and K⫹ secretion, 162 metabolic alkalosis due to, 182Q–183Q, 188E

299

Hypercalcemia, 163 of malignancy, 247, 248t, 266Q, 277E Hypercalciuria, idiopathic, 163 Hypercapnia, 121 Hyperchloremic metabolic acidosis, 174 Hypercomplex cells, of visual cortex, 42 Hyperemia active, 93 reactive, 93 Hyperglycemia, in diabetes mellitus, 245 Hyperkalemia, 159, 160t and aldosterone secretion, 239 in diabetes mellitus, 245 due to exercise, 182Q, 188E due to hypoaldosteronism, 162, 178 due to K⫹-sparing diuretics, 162 and NH3 synthesis, 173 Hypermagnesemia, 163 Hyperosmotic solution, 5, 25Q, 26Q, 28E–29E, 30E Hyperosmotic volume contraction, 147–148, 147t Hyperosmotic volume expansion, 147, 147t Hyperparathyroidism, 247, 248t Hyperpigmentation, due to hypoaldosteronism, 178 Hyperpolarization, 10 of cardiac muscle, 70 Hyperpolarizing afterpotential, 11 Hypersecretion, of gastrin, 212 Hypertension due to Conn’s syndrome, 183Q, 188E essential, plasma renin activity in, 273Q, 284E due to renal artery stenosis, 105Q, 111E–112E Hyperthermia, malignant, 56 Hyperthyroidism, 235, 236t, 259Q, 262E Hypertonic solution, 6 Hypertropia, 39 Hyperventilation due to diarrhea, 178 in high altitude, 135 hypoxemia and, 138Q, 142E in metabolic acidosis, 173 respiratory alkalosis due to, 268Q, 279E Hypoaldosteronism, 162, 177–178 Hypocalcemia, in respiratory alkalosis, 177 Hypochloremia, due to vomiting, 178 Hypokalemia, 159, 160t due to diarrhea, 179, 213 due to hyperaldosteronism, 162 due to thiazide and loop diuretics, 162 due to vomiting, 178 Hyponatremia, due to hypoaldosteronism, 178 Hypoparathyroidism, 247, 248, 248t, 257Q, 261E pseudo, 248, 248t, 257Q, 261E Hyposmia, 46 Hyposmotic solution, 5 Hyposmotic volume contraction, 147t, 148 hyposmotic volume expansion, 147t, 148 Hypotension in diabetes mellitus, 245 orthostatic baroreceptor reflex and, 96 after sympathectomy, 101Q, 108E due to hypoaldosteronism, 177, 178 Hypothalamic set point, for body temperature, 56 Hypothalamic–hypophysial portal system, 227

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300

Index

Hypothalamus in autonomic nervous system, 35 in heat loss, 55 and pituitary gland, 227 Hypothermia, 56 Hypothyroidism, 235, 236t Hypotonic solution, 6 Hypotonic urea, 24Q, 28E Hypoventilation due to COPD, 271Q, 282E in metabolic alkalosis, 175 Hypoxemia adaptation to chronic, 126 due to asthma, 138Q, 142E as cause of hyperventilation, 135, 138Q, 142E causes of, 128t defined, 127 in high altitude, 135 Hypoxia causes of, 128t and coronary circulation, 94 defined, 128 O2 transport in, 128 due to right-to-left cardiac shunt, 136Q, 138Q, 140E, 142E Hypoxic vasoconstriction, 130, 136Q, 140E, 274Q, 285E Hysteresis, 116, 116 Hz (hertz), 43 I I– (iodide), oxidation of, 232 I bands, 17, 17 I cells, 193, 207 I– (iodide) pump, 232, 233 I2 (iodine), organification of, 233 ICF (intracellular fluid), 144, 145, 145t measuring volume of, 145t, 146 shifts between compartments of, 146, 146–148, 147t Idiopathic hypercalciuria, 163 iffusion trapping, 172 IGF (insulin-like growth factors), 229, 229 IL-1 (interleukin-1), in fever, 56, 267Q, 279E IL-2 (interleukin-2), glucocorticoids and, 239 Ileal resection, 212 Immune response, glucocorticoid suppression of, 239 Inactivation gates, of Na⫹ channel, 7, 24Q, 28E Incisura, 85 inferior colliculus, in auditory pathways, 44 Inhibin, 251, 252, 258Q, 261E Inhibitory neurotransmitters, 12, 14, 16, 26Q, 29E Inhibitory postsynaptic potentials (IPSPs), 14, 25Q, 29E Inner ear, 43, 43–44 Inner hair cells, 44 Inositol 1,4,5-triphosphate (IP3) ␣1 receptors, 33, 58Q, 62E Inositol 1,4,5-triphosphate (IP3) mechanism, of hormone action, 224, 224t, 226, 259Q, 263E Inositol 1,4,5-triphosphate (IP3)-gated Ca2⫹ channels, 22 Inotropic agents negative, 75, 77 and cardiac output curve, 81, 265Q, 276E

positive, 75, 77 and cardiac output curve, 81, 81 Inotropic effect, negative, 105Q, 112E Inotropism, 75–76, 77 negative, 75, 77 positive, 75, 77 Inspiration muscles of, 115 volume and pressure during, 121 Inspiratory capacity, 114, 114 Inspiratory reserve volume (IRV), 113, 114 Inspired gas viscosity or density of, 119 Insulin, 243–245 actions of, 223t, 244, 244t and blood glucose, 243, 244 pathophysiology of, 245 secretion of, 222, 244, 244t regulation of, 243–244, 244t, 271Q, 282E Insulin receptor, 244, 270Q, 281E Insulin-like growth factors (IGF), 229, 229 Integral proteins, 1 Intensity, of sound, 43 Intention tremor, 52 ␣-Intercalated cells, 159 Intercalated disks, myocardial, 74, 105Q, 112E Intercellular connections, 1 intercostal muscles, in breathing external, 115 internal, 116 Interleukin-1 (IL-1), in fever, 56, 267Q, 279E Interleukin-2 (IL-2), glucocorticoids and, 239 Internal intercostal muscles, in breathing, 116 Interstitial cells of Cajal, 195 Interstitial fluid, 144, 145, 145t hydrostatic pressure of, 91 measuring volume of, 145t, 146 oncotic pressure of, 91 Intestinal crypts, 213 Intracellular buffers, 170 Intracellular fluid (ICF), 144, 145, 145t measuring volume of, 145t, 146 shifts between compartments of, 146, 146–148, 147t Intrafusal fibers, 47–48, 48, 60Q, 63E Intrapleural pressure, 116 during breathing cycle, 120, 120, 137Q, 141E measurement of, 120 Intrinsic factor secretion of, 202, 202t, 203, 216Q, 219E in vitamin B12 absorption, 269Q, 280E Inulin clearance, as measurement of GFR, 150 in tubular fluid, 184Q, 189E Inverse myotatic reflex, 49–50, 49t Inward current, 10, 269Q, 280E Iodide (I–), oxidation of, 232 Iodide (I–) pump, 232, 233 Iodine (I2), organification of, 233 Ion channels, 7 Ionotropic receptors, 16 IPSPs (inhibitory postsynaptic potentials), 14, 25Q, 29E Iron ferric, 124 ferrous, 123 absorption of, 210t, 214 Iron deficiency anemia, 214

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Index Irritable bowel syndrome, 199 Irritant receptors, 134 IRV (Inspiratory reserve volume), 113, 114 Islets of Langerhans, 242, 243t Isometric contractions, 19 Isoproterenol, and airway resistance, 119 Isosmotic solution, 5 Isosmotic volume contraction, 147, 147t Isosmotic volume expansion, 146, 146, 147t Isotonic contractions, 19, 20 Isotonic fluid water shifts between compartments due to, 147, 147t Isotonic solution, 6 Isovolumetric contraction, 78, 101Q, 107E ventricular, 273Q, 284E Isovolumetric relaxation, 78 ventricular, 85, 104Q, 106Q, 111E, 112E J Jacksonian seizures, 53 Joint receptors, in control of braething, 134 Juxtacapillary (J) receptors, 134 K K⫹ absorption of, 213 dietary, 161–162 reabsorption of, 160 shifts between ICF and ECF, 159, 159, 160t K⫹ balance, renal regulation of, 159–162, 160–161, 160t, 161t K⫹ concentration insulin and, 245 K⫹ equilibrium potential, 10, 10, 24Q, 28E K⫹ secretion, 161–162 by colon, 213 factors that change, 161, 161, 161t high-K⫹ diet and, 184Q, 189E mechanism of, 161, 161 spironolactone and, 180Q, 185E Ketoacid(s), 169 glucagon and, 243 insulin and, 245 Ketoacidosis, diabetic, 245, 269Q, 280E Ketoconazole, for Cushing’s disease, 241 17-Ketosteroids, 237, 242 Kf (filtration coefficient), 90, 101Q, 108E, 151 Kidneys, effect of autonomic nervous system on, 35t Kinocilium, 45, 45 Knee-jerk reflex, 49, 49, 49t, 267Q, 278E–279E K⫹-sparing diuretics, 159, 162 Kussmaul breathing, 173 L Lactase, 209, 210 Lactation, 256, 258Q, 262E Lactic acid, 169 Lactic acidosis, 135 Lactogenesis, 230 Lactose intolerance, 211 Laminar flow, 67 Language, 54 Laplace’s law, 118 Large intestinal motility, 198–199 Lateral geniculate body, 40, 41 Lateral geniculate cells, receptive fields of, 41–42

301

Lateral vestibulospinal tract, 51 “Leaky” junctions, 1 Learning, 54 Lecithin:sphingomyelin ratio, 118 Left atrial pressure, 69, 84 Left hemisphere, in language, 54 Left ventricular pressure, 77, 84 Left-to-right shunts, 274Q, 285E Left-to-right ventricular shunt, 101Q, 108E Length–tension relationship in skeletal muscle, 19–20, 20 in ventricles, 76–77, 77 Lens biconcave, 39 convex, 39 cylindrical, 39 refractive power of, 39 Leu-enkephalin, 195 Leydig cells, 250, 251 Ligand-gated channels, 7, 13 Linear acceleration, 44 Lingual lipases, 212 Lipid(s) absorption of, 210t, 212, 267Q, 278E digestion of, 210t, 212 malabsorption of, 210t, 212 metabolism, 215 Lipid bilayer, of cell membrane, 1 Lipid-soluble substances, and cell membrane, 1 Lipocortin, 239 Lipolysis, glucagon and, 243 ␤-Lipotropin, 223t, 228, 228 Lithium, 271Q, 282E Lithocholic acid, 209 Liver function bilirubin metabolism, 214, 215 detoxification, 215 metabolic functions of, 214–215 Longitudinal muscle, 190, 191 in gastrointestinal motility, 195 Long-term memory, 54 Long-term potentiation, 14 Loop diuretics and Ca2⫹ excretion, 163 for hypercalcemia, 277E isosthenuric urine due to, 168 and K⫹ secretion, 162 major effects of, 177t mechanism of action of, 177t site of action of, 158, 177t Loop of Henle countercurrent multiplication in, 164 thick ascending limb of Na⫹ reabsorption in, 156, 156 in K⫹ reabsorption, 158, 160 in urine production, 164–166, 167 Lower esophageal sphincter, 196, 197 Low-K⫹ diet, 162 Lumbar puncture, 54 Lumen-positive potential difference, 158 Luminal anions, and K⫹ secretion, 162 Lung capacities, 114, 114–115 Lung compliance, 116, 116–117, 117 Lung stretch receptors, 134 Lung volumes, 113–114, 114 and airway resistance, 119 during breathing cycle, 120, 120, 121 Lung–chest wall compliance, 117

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302

Index

Luteal phase, of menstrual cycle, 254, 255, 257Q, 261E Luteinizing hormone (LH) actions of, 223t in menstrual cycle, 254, 255 origin of, 223t in regulation of ovary, 253 regulation of secretion of, 265Q, 276E in regulation of secretion of, 251 in regulation of testes, 251, 252 structure of, 228 in testosterone synthesis, 250, 251 variation over life span, 252 Luteinizing hormone (LH) surge, 222, 254, 257Q, 261E 17,20-Lyase, 271Q, 282E Lymph, 91 M M line, 17 Macula densa, in tubuloglomerular feedback, 149 Magnesium (Mg2⫹), renal regulation of, 163 Malabsorption, of lipids, 212 Male phenotype, 250, 250 Male reproduction, 250–252, 251, 252 Male sex organs, effect of autonomic nervous system on, 35t Malignancy, humoral hypercalcemia of, 247, 248t, 266Q, 277E Malignant hyperthermia, 56 Maltase, 209 Mannitol, and extracellular fluid volume, 144–145, 181Q, 186E Many-to-one synapses, 14 MAO (monoamine oxidase), 15 Mean arterial pressure, 68, 69 set point for, 86 Mean pressures in cardiovascular system, 68 Mean systemic pressure, 79, 80, 102Q, 103Q, 108E, 109E, 110E Mechanoreceptors, 36, 38t Medulla in autonomic nervous system, 35 in control of breathing, 133 Medullary respiratory center, 133 Medullary reticulospinal tract, 51 Megacolon, 199 Meissner’s corpuscle, 38t Meissner’s plexus, 190, 191 Melanocyte-stimulating hormone (MSH), 223t, 228 Membrane(s) cell structure of, 1 transport across, 2–5, 2t, 4, 5 semipermeable, 7–8, 8, 23Q, 27E Membrane potential, resting of cardiac muscle, 70 of skeletal muscle, 10, 10 Memory, 54 Menses, 254, 255 Menstrual cycle, 254, 255 follicular phase of, 254, 255 luteal phase of, 254, 255, 257Q, 261E menses in, 254, 255 negative and positive feedback control of, 254t ovulation in, 254, 255, 266Q, 277E MEPP (miniature end plate potential), 13 Merkel’s disk, 38t

Metabolic acidosis, 173–174, 173t acid–base map of, 175 due to carbonic anhydrase inhibitor, 273Q, 284E causes of, 174t due to chronic renal failure, 183Q, 188E, 274Q, 285E due to diabetes mellitus, 183Q, 188E due to diarrhea, 178–179, 182Q, 185E, 266Q–267Q, 278E hyperchloremic, 174 due to hypoaldosteronism, 178 respiratory compensation for, 173, 176t, 274Q, 285E Metabolic alkalosis, 173t, 174–175 acid–base map of, 175 causes of, 174t due to hyperaldosteronism, 182Q–183Q, 188E respiratory compensation for, 175, 176t, 182Q, 187E due to vomiting, 174, 178, 179, 183Q, 189E, 203, 271Q, 282E Metabolic effects, of thyroid hormone, 235 Metabolic hypothesis, of local control of blood flow, 93 Metabolism bilirubin, 214, 215 carbohydrate, 214 lipid, 215 protein, 215 Metabotropic receptor, 16 Metarhodopsin II, 41, 42, 59Q, 62E Metarterioles, 89 Met-enkephalin, 195 Methemoglobin, 124 3-Methoxy-4-hydroxymandelic acid, 15, 31 3-Methoxy-4-hydroxyphenylglycol (MOPEG), 15 Mg2⫹(magnesium), renal regulation of, 163 Micelles bile salts and, 208, 208 in lipids absorption, 212 and vitamin D, 217Q, 220E Microcirculation, 89–92, 90 Midbrain, in autonomic nervous system, 35 Middle ear, 43 Migraine headaches, 94 Migrating myoelectric complex, in gastrointestinal motility, 197 Mineralocorticoids, 237, 239 Miniature end plate potential (MEPP), 13 Minimum urine pH, 172 Minute ventilation, 114 MIT (monoiodotyrosine), 233, 233, 286E Mitochondria, myocardial, 75 Mitral cells, in the olfactory bulb, 46 Mitral valve closure of, 83, 84 opening of, 84, 85 Molecular layer, of cerebellar cortex, 52 Monoamine oxidase (MAO), 15 Monoglycerides, absorption of, 212 Monoiodotyrosine (MIT), 233, 233, 286E Monosaccharides, absorption of, 210, 210–211, 285E MOPEG (3-methoxy-4-hydroxyphenylglycol), 15 Mossy fibers, 52 Motilin, 197 Motoneuron(s), 47 ␣–, 47, 48, 49

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Index in stretch reflex, 49, 49 convergence on, 50 divergence to, 50 ␥–, 47, 48, 49 in stretch reflex, 49 large, 47 small, 47 Motoneuron pool, 47 Motor aphasia, 54 Motor centers, 50–51 Motor cortex, 53, 58Q, 62E Motor homunculus, 53, 58Q, 62E Motor pathways, 50–51 Motor systems, 47–53 basal ganglia in, 52–53 brain stem control of posture in, 50–51 cerebellum in, 51–52 motor cortex in, 53 motor unit in, 47 muscle reflexes in, 49, 49–50, 49t muscle sensors in, 47–48, 48 spinal organization of, 50 Motor unit, 47 MSH (melanocyte-stimulating hormone), 223t, 228 Mucous cells, in gastric secretion, 202, 202t, 203 Mucous gastric secretion, 202t Müllerian ducts, 250 Multiple myeloma, 266Q, 277E Multi-unit smooth muscle, 20–21 Muscarinic receptor(s), 33t, 34, 57Q, 61E drugs that act on, 34t Muscarinic receptor blocker, and gastric secretion, 203 Muscle contraction cardiac, 75–76, 76 isometric, 19 isotonic, 19, 20 skeletal muscle, 18, 18–19, 19 Muscle end plate, ACh at, 13–14, 25Q, 29E Muscle fibers, 47, 48 Muscle length, detection of, 47 Muscle reflexes, 49, 49–50, 49t Muscle relaxation cardiac, 75 skeletal, 19 Muscle sensors, 47–48, 48 Muscle spindles, 48, 48 Muscle tension, 19–20, 20 detection of, 47 Muscle weakness, K⫹ concentration and, 11, 26Q, 30E Muscles receptors, in control of braething, 134 Muscularis mucosa, of GI tract, 190, 191 Myasthenia gravis, AChE receptors in, 14, 24Q, 28E Myelinated axon, 11, 12, 25Q, 28E Myeloma, multiple, 266Q, 277E Myenteric plexus, 190, 191, 191 Myocardial cell structure, 74–75 Myocardial contractility, 75–76, 76 in baroreceptor reflex, 87 Ca2⫹ and, 75, 104Q, 110E and cardiac output, 103Q, 109–110E factors that decrease, 76, 105Q, 112E factors that increase, 75 in Frank–Starling relationship, 77, 100Q, 107E and ventricular pressure–volume loop, 78, 78 Myocardial O2 consumption, 82, 104Q, 111E

303

Myofibrils, 16, 17 Myogenic hypothesis, of local control of blood flow, 93 renal, 149 Myopia, 39 Myosin, 16–17 in excitation–contraction coupling, 18, 19 Myosin cross-bridges, 18, 19 Myosin-light-chain kinase, 21, 22 Myotatic reflex, 49, 49, 49t inverse, 49–50, 49t N Na⫹ channels activation and inactivation gate of, 7, 24Q, 28E complete blockade of, 25Q, 29E Na⫹ current, inward, 103Q, 110E Na⫹ diffusion potential, 7–8, 8 Na⫹ equilibrium potential, 8 in nerve action potential, 10, 10–11, 24Q, 28E Na⫹ gradient, 4 Na⫹ reabsorption, 156–157, 156–159, 158 Na⫹–Ca2⫹ countertransport, 5, 5 Na⫹–Ca2⫹ exchange, 5, 5 NaCl, absorption of, 213 Na⫹–Cl– cotransporter, 158, 158 NaCl intake, water shifts between compartments due to, 147, 147t NaCl regulation, 155–159, 156–157, 158 Na⫹–dependent cotransport of amino acids, 211, 211, 216Q, 219E of carbohydrates, 210 Na⫹–glucose cotransport, 4, 4, 25Q, 29E, 153 Na⫹–glucose cotransporter 1 (SGLT 1), 210 Na⫹–H⫹ exchange, 157 Na⫹–K⫹ pump, 3, 210 Na⫹–K⫹–2Cl– cotransport, 4, 271Q, 282E Na⫹–K⫹–2Cl– cotransporter, 158, 158, 160, 164 Na⫹,K⫹–ATPase, 3, 4, 25Q, 29E Na⫹–phosphate cotransport, 163 Near point, 39 Nearsightedness, 39 Negative chronotropic effect, 73 Negative dromotropic effect, 73 Negative feedback, for hormone secretion, 222 Negative inotropic agents, 75, 77 and cardiac output curve, 81, 265Q, 276E Negative inotropic effect, 105Q, 112E Neonatal respiratory distress syndrome, 118, 136Q, 140E Neostigmine, and neuromuscular transmission, 13, 13t, 14 Nephrogenic diabetes insipidus, 166, 168, 168t, 270Q, 271Q, 281E, 282E Nephron in calcium regulation, 163 concentration and dilution of urine in, 163–168, 164, 165, 166, 168t disorders related to, 168t effects of diuretics on, 177t in K⫹ regulation, 159–162, 160–161, 160t, 161t in magnesium regulation, 163 in Na⫹ reabsorption, 156–157, 156–159, 158 in NaCl regulation, 156–157, 156–159, 158 in phosphate regulation, 163 in urea regulation, 162–163 Nephrotic syndrome, 282E Nernst equation, 8–9 Nerve fiber types, 36t

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304

Index

Neurocrines, 192, 194–195 Neuromuscular junction, 12, 12–14, 13t, 24Q, 28E Neuromuscular transmission, 12, 12–14, 13t Neurophysiology, 31–63 of autonomic nervous system, 31–35, 32, 32t–35t of blood–brain barrier and cerebrospinal fluid, 54–55, 55t of higher functions of cerebral cortex, 53–54 of motor systems, 47–53 motor unit in, 47 muscle sensors in, 47–48, 48 muscle reflexes in, 49, 49–50, 49t spinal organization of, 50 brain stem control of posture, 50–51 cerebellum in, 51–52 basal ganglia in, 52–53 motor cortex in, 53 of sensory system(s), 35–47 sensory receptors in, 35–38, 36t, 37 somatosensory, 38–39, 38t vision as, 39–42, 40–42, 40t audition as, 43, 43–44 vestibular, 44–46, 45 olfaction as, 46 taste as, 46–47 of temperature regulation, 55–56 Neurotransmitters, 15, 15–16 of autonomic nervous system, 31 excitatory, 12 inhibitory, 12, 14, 16, 26Q, 29E release of, 12 NH3 (ammonia) synthesis, 173 NH4⫹ (ammonium cation), H⫹ excretion as, 172, 173 Nicotinic receptors, 33t, 34 drugs that act on, 34t and epinephrine secretion, 58Q, 62E on ligand-gated channels, 7 at neuromuscular junction, 12 Night blindness, 41 Nitric oxide (NO), 16, 92 Nitric oxide (NO) synthase, 16 Nitrous oxide (N2O), perfusion-limited exchange of, 122 NMDA (N-methyl-D-aspartate) receptor, 16 N-methyl-D-aspartate (NMDA) receptor, 16 NMN (normetanephrine), 15 NO (nitric oxide), 92 Nociception, 39 Nociceptors, 36, 39 Nodes of Ranvier, 11, 12 Nonadrenergic, noncholinergic neurons, 31 Nonionic diffusion, 155 Nonvolatile acids, 169 Norepinephrine, 14, 15 and adenylate cyclase, 58Q, 62E in autonomic nervous system, 31 in hemorrhage, 99 synthetic pathway for, 15 Normetanephrine (NMN), 15 Noxious stimuli, 47 Nuclear bag fibers, 48, 48, 60Q, 63E Nuclear chain fibers, 48, 48 Nucleus cuneatus, 38 Nucleus gracilis, 38 Nystagmus, 45–46, 58Q, 62E postrotatory, 46

O O2

in control of breathing, 133 diffusion-limited gas exchange, 123 dissolved, 122 partial pressure of, 122–123, 123t alveolar, 128, 135 arterial, 135 perfusion-limited exchange, 122–123 for ventilation/perfusion defect, 139Q, 143E O2 capacity, 124 O2 consumption cardiac, 83, 104Q, 111E during exercise, 138Q, 142E O2 content, 124 O2 delivery, 128 O2 diffusion, 123 O2 transport, 123–128 hemoglobin in, 123–124 hemoglobin–O2 dissociation curve, 124–125, 125 changes in, 125–127, 126, 127 and hypoxemia, 127–128, 128t and hypoxia, 128 O2-binding capacity, 124 Octreotide, 230 Odorant molecules, 46 Off-center, on-surround pattern, 42 Ohm’s law, 66 Oil/water partition coefficient, 3, 25Q, 29E Olfaction, 46, 59Q, 62E Olfactory bulb, 46 Olfactory nerve, 46 Olfactory pathways, 46 Olfactory receptor neurons, transduction in, 46 Olfactory receptor proteins, 46 Olfactory system, 46, 59Q, 62E Omeprazole, and gastric secretion, 206 On-center, off-surround is one pattern, 42 Oncotic pressure, 6 Bowman’s space, 151 capillary, 91 glomerular, 151 interstitial fluid, 91 One-to-one synapses, 14 Opsin, 40 Optic chiasm, 40 lesion of, 40, 41, 59Q, 63E Optic nerve, 39 lesion of, 40, 41, 58Q, 61E Optic pathways, 40, 41 Optic tract, 40 lesion of, 40, 41, 58Q, 62E Optics, 39 Orad region, of stomach, 197 Organ of Corti, 44, 57Q, 61E auditory transduction by, 43, 44 Organic phosphates, as intracellular buffers, 170 Orthostatic hypotension after sympathectomy, 101Q, 108E baroreceptor reflex and, 96 due to hypoaldosteronism, 178 Osmolarity, 5, 26Q, 30E of body fluids, 146–148, 147t calculation of, 5, 25Q, 28E–29E plasma regulation of, 163, 164 of urine, 180Q, 185E

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Index Osmole, ineffective, 6 Osmosis, 5–7, 6 Osmotic diarrhea, due to lactose intolerance, 211 Osmotic exchangers, 164 Osmotic gradient, corticopapillary, 163–164, 167 Osmotic pressure, 5–7 effective, 6–7 Ossicles, 43 Osteomalacia, 214, 248 Outer ear, 43 Outer hair cells, 44 Outward current, 10 Oval window, 43 Ovary, regulation of, 253, 254t Overshoot, of action potential, 11 Ovulation, 254, 255, 266Q, 277E lactation and, 256 Oxygen (see O2) Oxyhemoglobin, 124 as intracellular buffer, 170 Oxytocin, 223t, 232 actions of, 223t, 232 mechanism of action of, 266Q, 277E regulation of secretion of, 232, 258Q, 259Q, 261E, 263E P P wave, 69, 69 absent, 100Q, 107E, 270Q, 281E additional, 102Q, 109E P50, and hemoglobin-O2 dissociation curve, 125, 125, 126, 137Q, 141E, 265Q, 276E Pacemaker, cardiac, 71 in AV node, 100Q, 107E latent, 71 Pacemaker potential, in SA node, 103Q, 110E Pacinian corpuscles, 38t, 47, 270Q, 281E PAH (see Para-aminohippuric acid [PAH]) Pain, 39 fast, 39 flexor withdrawal reflex to, 50 referred, 39 slow, 39 Pancreas, endocrine, 242–245, 242t–244t Pancreatic cholera, 195 Pancreatic enzymes, 208 Pancreatic juice, 206 Pancreatic lipases, 212 Pancreatic proteases, 211 Pancreatic secretion, 199t, 206–208, 207, 217Q, 220E composition of, 206, 207 flow rates for, 206, 207 formation of, 206–207, 207 inhibition of, 199t modification of, 206–207, 207 stimulation of, 199t, 207–208 Papillae, 46 Para-aminohippuric acid (PAH) clearance of, 149, 182Q, 187E excretion of, 154, 154 filtered load of, 154, 154 and renal blood flow, 182Q, 187E secretion of, 154, 154 titration curve, 154 transport maximum (Tm) curve for, 154, 154, 181Q, 187E in tubular fluid, 184Q, 189E, 272Q, 283E

305

Paracrines, 192, 194 Parallel fibers, of cerebellar cortex, 52 Parallel resistance, 66 Paraplegia, 51 Parasympathetic effects, on heart rate and conduction velocity, 73 Parasympathetic ganglia, 31 Parasympathetic nervous system of GI tract, 190–191 organization of, 31, 32, 32t Parasympathetic stimulation and airway resistance, 119 and myocardial contractility, 76 of saliva, 201, 202 Parathyroid adenoma, 247 Parathyroid hormone (PTH) actions of, 223t, 247 and Ca2⫹ reabsorption, 163 in calcium reabsorption, 247, 259Q–260Q, 264E in calcium regulation, 246, 246t, 247 and phosphate reabsorption, 163 renal effects of, 169t, 183Q, 188E secretion of, 247 Parathyroid hormone-related peptide (PTH-rp), 247 Parietal cells, 202, 202t, 203 H⫹ secretion by, 202, 202t, 203 mechanism of, 203, 203–204 agents that stimulate and inhibit, 204 Parkinson’s disease, 15, 26Q, 30E Parotid glands, 200 Partial pressure(s) of carbondioxide, 122, 123t Dalton’s law of, 122 of oxygen, 122, 123t Partial pressure differences, 122 Parturition, 256 Passive tension, 19, 20 Patent ductus arteriosus, 131 PBS (Bowman’s space hydrostatic pressure), 151 PCO2 arterial, 134, 135, 138Q–139Q and HCO3– reabsorption, 171 and hemoglobin-O2 dissociation curve, 125–127 venous, 135 Pelvic nerve, 191 Pepsin, 211 Pepsinogen, 202, 202t, 203 Peptic ulcer disease, 205–206, 218Q, 221E Peptide hormone, synthesis of, 222 Perchlorate anions, 232 Perfusion-limited exchange, 122, 123 Perilymph, 43, 44 Peripheral proteins, 1 Peristalsis, 196 esophageal, 196–197 gastric, 197 large intestinal, 198–199 small intestinal, 197–198, 217Q, 220E Peristaltic contractions esophageal primary, 196 secondary, 196 in small intestine, 198 Peritubular capillaries, Starling forces in, 157 Permeability of cell membrane, 3, 25Q, 29E of ion channels, 7

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306

Index

Pernicious anemia, 214 PGC (glomerular capillary hydrostatic pressure), 151 pH and buffers, 170 calculation of, 170 and gastric secretion, 205 and hemoglobin- O2 dissociation curve, 127 urine acidic, 155 alkaline, 155 minimum, 172 of venous blood, 139Q, 143E Phasic contractions, in gastrointestinal motility, 195 Phasic receptors, 37 Phenotypic sex, 249, 250 Phenoxybenzamine, 60Q, 63E Phentolamine, for pheochromocytoma, 265Q, 276E Phenylalanine, and gastrin secretion, 193 Pheochromocytoma hypertension due to, 111–112E phenoxybenzamine for, 60Q, 63E phentolamine and propranolol for, 265Q, 276E signs and symptoms of, 265Q, 276E vanillylmandelic acid excretion with, 15, 31, 276E Phosphate(s) as extracellular buffers, 169 as intracellular buffers, 170 renal regulation of, 163 PTH and, 247 as urinary buffer, 169 Phosphaturia, 163 Phospholamban, 76 Phospholipids, in cell membrane, 1 Phosphoric acid, 169 Photoisomerization, 41 Photoreception, 40–41, 42, 59Q, 62E, 275Q, 286E Photoreceptors, 36, 57Q, 61E Physiologic dead space, 113–114 Physiologic shunt, 122 PIF (prolactin-inhibiting factor), 15, 223t (see also Dopamine) Pigment epithelial cells, 39 Pink puffers, 121 Pinocytosis, 90 Pituitary gland, 227–232 anterior, 227 hormones of, 227–231, 228–230, 231t, 267Q, 278E removal of, 267Q, 278E posterior, 228 hormones of, 231–232 and relationship with hypothalamus, 227–228 pK, of buffers, 169 Plasma, 144, 145, 145t Plasma osmolarity regulation of, 163, 164, 165 sweating and, 182Q, 188E Plasma volume, 145, 145, 145t Plasma-like tubular fluid, 272Q, 283E Plateau phase, of action potential, 71, 269Q, 280E Pneumotaxic center, 133 Pneumothorax, 117 PO2, 122–123, 123t alveolar, 128, 135 arterial, 135

Poiseuille’s equation, 66 Poiseuille’s law, 119 Polydipsia, 168t Polyuria, due to hypercalcemia, 266Q, 277E POMC (pro-opiomelanocortin), 228, 238 Pontine reticulospinal tract, 51 Pontocerebellum, 51 Positive chronotropic effects, 73, 74 Positive cooperativity, 125 Positive dromotropic effects, 73 Positive feedback, for hormone secretion, 222, 265Q, 276E Positive inotropic agents, 75, 77 and cardiac output curve, 81, 81 Positive inotropism, 75, 76, 76 Positive staircase, 75 Posterior pituitary gland, 228 hormones of, 231–232 Postextrasystolic potentiation, 75 Postganglionic neurons, 31 Postrotatory nystagmus, 46, 62E Postsynaptic cell membrane, 12, 25Q, 29E end plate potential in, 13 Postsynaptic potentials excitatory, 14 inhibitory, 14, 25Q, 29E Post-tetanic potentiation, 14 Posture, brain stem control of, 50–51 Potassium (see K⫹) Potentiation of gastric H⫹ secretion, 204–205 long-term, 14 postextrasystolic, 75 post-tetanic, 14 Power stroke, 19 PR interval, 69, 69–70, 100E PR segment, 108E Prazosin, 57Q, 61E Precapillary sphincter, 89 Preganglionic neurons, 31 Pregnancy, 255–256 hormone levels during, 256 human chorionic gonadotropin in, 255, 271Q, 282E–283E lactation suppression during, 258Q, 262E Pregnenolone, 237, 251 Preload, 19 ventricular, 76 and ventricular pressure–volume loop, 78, 78 Premotor cortex, 53 Preprohormone, 222 Prerenal azotemia, 150 Presbyopia, 39 Pressure gradient, atmosphere, 120, 120 Pressure profile, in blood vessels, 67–68 Presynaptic terminal, 12 Primary active transport, 2t, 3–4, 26Q, 30E Primary motor cortex, 53 Primordial follicle, 254 Principal cells in K⫹ regulation, 161, 161 in Na⫹ reabsorption, 159 Progesterone actions of, 223t, 254 during menstrual cycle, 254, 255, 257Q, 261E during pregnancy, 256 synthesis of, 236, 237, 253, 253

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Index Prohormone, 222 Proinsulin, 243 Prolactin, 223t, 230, 230–231, 231t, 256 Prolactin-inhibiting factor (PIF), 15, 223t Prolactinomas, 231, 258Q, 261E Pro-opiomelanocortin (POMC), 228, 238 Propagation, of action potential, 11, 12 Propranolol contraindication to, 58Q, 61E mechanism of action of, 104Q, 105Q, 111E, 112E for pheochromocytoma, 265Q, 276E Propylthiouracil, 232, 259Q, 263E, 269Q, 280E Prostacyclin, in blood flow regulation, 94 Prostaglandins in blood flow regulation, 94 in fever, 56 and gastrin secretion, 204, 205 Prostate, 5␣-reductase and, 273Q, 284E Protein hormones, synthesis of, 222 Protein kinase C, 225 Protein(s) absorption of, 210t, 211, 211–212 in cell membrane, 1 digestion of, 210t, 211 integral, 1 as intracellular buffers, 170 metabolism, 215 peripheral, 1 Proton (see H⫹) Proton pump, 4 Proximal tubular reabsorption, ECF volume and, 158 Proximal tubule(s) and Ca2⫹ reabsorption, 163 glomerulotubular balance in, 156, 157–158, 158 in K⫹ reabsorption, 159 Na⫹ reabsorption in, 156–157, 156–158, 158 Na⫹–glucose cotransport in, 153 PAH secretion in, 154 reabsorption of filtered HCO3– in, 170–171, 171 in urine production, 164, 167 Pseudohypoparathyroidism, 248, 248t, 257Q, 261E PTH-rp (parathyroid hormone-related peptide), 247 Puberty, 252 Pulmonary artery pressure, 76 Pulmonary blood flow (Q), 129 in different regions of lung, 130 distribution of, 130 during exercise, 135 gravitational forces and, 130, 136Q–137Q regulation of, 130 Pulmonary circulation, 129–131 Pulmonary embolism, V/Q ratio in, 132, 137Q, 141E Pulmonary fibrosis diffusion-limited exchange during, 123 FEV1 in, 115, 115 lung compliance in, 117 PaCO2 in, 138Q–139Q, 143E Pulmonary vascular resistance, 130 fetal, 130 Pulmonary vasoconstriction, in high altitudes, 135 Pulmonary wedge pressure, 69 Pulmonic valve, closure of, 85

307

Pulse pressure, 68, 68, 100Q, 103Q, 104Q, 107E, 110E, 111E capacitance and, 273Q, 284E extrasystolic beat and, 100Q, 107E Purkinje cell layer, of cerebellar cortex, 52 Purkinje cells, 52 Purkinje system, action potentials of, 70–71 Pursed lips intrapleural pressure, 121 Pyramidal tracts, 50 Pyrogens, 56 Q Q (see Pulmonary blood flow [Q]) QRS complex, 69, 70, 273Q, 283E QT interval, 69, 70, 269Q, 280E R Radiation, heat loss by, 55 Rapid eye movement (REM) sleep, 54 Rapidly adapting receptors, 37 RBCs (red blood cells), lysis of, 24Q, 28E RBF (renal blood flow), 149, 182Q, 187E Reabsorbed substance, transport maximum (Tm) curve for, 153, 153–154 Reabsorption, 152, 152–153 of filtered HCO3–, 170–173, 171–172, 173 of glucose, 153, 153, 267Q, 278E of Na⫹, 156–157, 156–159, 158 Reabsorption rate, 152–153 Reactive hyperemia, 93 Rebound phenomenon, 52 Receptive field, 36 Receptive relaxation, of stomach, 197, 216Q, 219E Receptive visual fields, 41–42 Receptor potential, 37, 37, 59Q, 63E Receptor potentials in pacinian corpuscle, 270Q, 281E Recruitment of motor units, 47 Rectosphincteric reflex, 198 Rectum, 198 Recurrent inhibition, 50 Red blood cells (RBCs), lysis of, 24Q, 28E 5␣-Reductase and prostate, 273Q, 284E in testosterone synthesis, 250, 251, 260Q, 264E, 268Q, 279E 5␣-Reductase inhibitors, 250 Re-esterification, 212 Referred pain, 39 Reflection coefficient, 6–7, 25Q, 28E–29E Reflexes, muscle, 49, 49–50, 49t Refractive errors, 39 Refractive power, 39 Refractory period(s), 10, 11 absolute, 10, 11, 24Q, 28E cardiac, 72–73, 73 cardiac, 72–73, 73 relative, 10, 11 Relative clearance, 154–155 Relative refractory period (RRP), 10, 11 cardiac, 72–73, 73 REM (rapid eye movement) sleep, 54 Renal arterioles vasoconstriction of, 149 vasodilation of, 149 Renal artery stenosis, 100Q, 105Q, 107E, 111E Renal blood flow (RBF), 149, 182Q, 187E

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308

Index

Renal clearance, 148, 182Q, 187E of glucose, 271Q, 281E–282E Renal compensation for respiratory acidosis, 176, 176t, 270Q, 281E for respiratory alkalosis, 176–177, 176t, 182Q, 187E Renal failure, chronic metabolic acidosis due to, 183Q, 188E, 274Q, 285E and PTH, 248, 248t and vitamin D, 258Q–259Q, 262E Renal perfusion pressure in arterial pressure regulation, 87 hemorrhage and, 268Q, 279E vomiting due to, 178 Renal physiology, 144–189 body fluids, 144–148, 145, 145t, 146, 147t calcium regulation in, 163 with diarrhea, 178–179 and diuretics, 177t glomerular filtration rate in, 150–151, 151, 152t in hypoaldosteronism, 177–178 integrative examples of, 177–179, 179 K⫹ regulation in, 159, 159–162, 160–161, 160t, 161t magnesium regulation in, 163 NaCl regulation in, 155–159, 156–157, 158 phosphate regulation in, 163 reabsorption and secretion in, 152, 152–155, 153, 154 renal blood flow in, 149 renal clearance in, 148 renal hormones in, 169t urea regulation in, 162–163 urine concentration and dilution in, 163–168, 164, 165, 166 disorders related to, 168t with vomiting, 178, 179 Renal plasma flow (RPF), 149, 152t, 182Q, 187E Renal regulation of calcium, 163 of K⫹, 159–162, 160–161, 160t, 161t of magnesium, 163 of NaCl, 155–159, 156–157, 158 of phosphate, 163 of urea, 162–163 Renal tubular acidosis (RTA), type 1, 174t Renal tubular acidosis (RTA), type 2, 174t Renal tubular acidosis (RTA), type 4, 173, 174t Renal tubule, PTH and, 183Q, 188E Renin, 87, 88, 239 Renin activity, plasma, in essential hypertension, 273Q, 284E Renin–angiotensin–aldosterone system in arterial pressure regulation, 87–88, 88 in hemorrhage, 99, 105Q, 112E Renshaw cells, 50 Repolarization of cardiac muscle, 70, 272Q, 283E Repolarization, of action potential, 11, 25Q, 28E Reproduction female, 253–256, 254t, 255, 256 male, 250–252, 251, 252 Residual volume (RV), 113, 114 after maximal expiration, 137Q, 141E and functional residual capacity, 273Q, 284E measurement of, 140E Resistance airway, 119, 137Q, 141E

arteriolar, 102Q, 109E exercise and, 97 and arterial pressure, 102Q, 109E parallel, 66 pulmonary vascular, 130 series, 66–67 vascular, 66–67 blood vessel radius and, 66, 100Q, 107E in pumonary circulation, 130 blood vessel radius and, 268Q, 279E in pumonary circulation fetal, 130 Respiratory acidosis, 173t, 175–176 acid–base map of, 175 causes of, 174t due to COPD, 183Q, 188E renal compensation for, 176, 176t, 270Q, 281E Respiratory alkalosis, 173t, 176–177 acid–base map of, 175 causes of, 174t in high altitude, 274Q, 285E in high altitudes, 135 due to hyperventilation, 268Q, 279E renal compensation for, 176–177, 176t, 182Q, 187E Respiratory compensation for metabolic acidosis, 173, 176t, 274Q, 285E for metabolic alkalosis, 175, 176t, 182Q, 187E Respiratory compliance, 116, 116–117, 117 Respiratory distress syndrome, neonatal, 118, 136Q, 140E Respiratory effects, of thyroid hormone, 235 Respiratory physiology CO2 transport in, 128–129, 129 control of breathing in, 132–134, 133t during exercise, 134–135, 135t gas exchange in, 122–123 with high altitude, 135, 135t lung volumes and capacities in, 113–115, 114, 115 mechanics of breathing muscles of inspiration, 115 muscles of expiration, 115–116 respiratory compliance in, 116, 116–117, 117 surface tension of alveoli and surfactant, 117–118, 118 pressure, airflow, and resistance in, 118–119 breathing cycle in, 120, 120–121 with lung diseases, 121, 121t oxygen transport in, 122–128, 125, 126, 127, 128t pulmonary circulation in, 129–131 and ventilation/perfusion defects, 131–132, 132t Resting membrane potential, 9 of cardiac muscle, 70 of skeletal muscle, 10, 10 Retching, 199 Reticulospinal tract medullary, 51 pontine, 51 Retina, layers of, 39, 40, 40t Retinal, 40 Retropulsion, in gastric mixing and digestion, 197 Reverse T3 (rT3), 234 Reynolds number, 67, 108E Rhodopsin, 40, 42 Rickets, 214, 248 Right atrial pressure, 76, 77 and end-diastolic volume, 103Q, 110E Right hemisphere, in language, 54

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Index Right-to-left shunts, 136Q, 138Q, 140E, 142E Rigor, 19, 26Q, 30E Rods, 39, 40t, 57Q, 61E photoreception in, 40–41, 42 Rotation, vestibular system during, 45, 45, 59Q, 63E RPF (renal plasma flow), 149, 152t, 182Q, 187E RRP (relative refractory period), 10, 11 cardiac, 72–73, 73 rT3 (reverse T3), 234 RTA (renal tubular acidosis), type 1, 174t RTA (renal tubular acidosis), type 2, 174t RTA (renal tubular acidosis), type 4, 173, 174t Ruffini’s corpuscle, 38t Ryanodine receptor, 18 S S cells, 194, 207 SA (sinoatrial) node action potentials of, 71, 71–72 pacemaker potential in, 103Q, 110E Saccule, 44 Salicylic acid, 155, 169 as cause of metabolic acidosis, 174t as cause of respiratory alkalosis, 174t Saliva, 199–202 composition of, 199t, 200, 200, 217Q, 220E, 266Q, 277E flow rates for, 201 formation of, 200, 200–201 functions of, 199–200 hypotonic, 201 inhibition of, 199t, 271Q, 282E modification of, 200, 201 regulation of production of, 201, 201–202 stimulation of, 199t Salivary ducts, 201 Salivary glands, 200 Saltatory conduction, 11, 12 Sarcolemmal membrane, 17 Sarcomere, 16 myocardial, 74 length of, 76 Sarcoplasmic and endoplasmic reticulum Ca2⫹ATPase (SERCA), 4, 19 Sarcoplasmic reticulum (SR), 16, 17, 18 myocardial, 75 Saturation, in carrier-mediated transport, 3 Scala media, 43, 44 Scala tympani, 43, 44 Scala vestibuli, 43, 44 Schizophrenia, 15 Second heart sound, 85, 102Q, 109E, 275Q, 286E Second messengers, 224–227, 224t, 225–227 Secondary active transport, 2t, 4, 4–5, 5, 26Q, 30E Second-order neurons, 37 Secreted substance, transport maximum (Tm) curve for, 154, 154 Secretin, 192, 192t, 193–194 actions of, 192t, 194 and pancreatic secretion, 207 stimulus for the release of, 192t, 194 Secretion of bile, 199t, 208–209 of electrolytes, 213 gastric (see Gastric secretion) of K⫹, 213 of PAH, 154, 154 pancreatic, 199t, 206–208, 207, 217Q, 220E

309

renal, 152, 152–153 of water in intestine, 213 Secretion rate, renal, 152–153 Secretory diarrhea, 214 Segmentation contractions of large intestine, 198 of small intestine, 198 Seizures, Jacksonian, 53 Selectivity, of ion channels, 7 Semicircular canals, 43, 44, 45, 45 Semilunar valves, closure of, 85 Semipermeable membrane, 7–8, 8, 23Q, 27E Sensory aphasia, 54 Sensory homunculus, 38 Sensory pathways, 37–38 Sensory receptors, 35–38, 36t, 37 adaptation, 37 types of, 36 Sensory systems, 35–47 audition as, 43, 43–44 olfaction as, 46 sensory receptors in, 35–38, 36t, 37 somatosensory, 38–39, 38t taste as, 46–47 vestibular, 44–46, 45 vision as, 39–42, 40–42, 40t Sensory transducers, 35–38, 36t, 37 Sensory transduction, 36–37, 37 SERCA (sarcoplasmic and endoplasmic reticulum Ca2⫹-ATPase), 4, 19 Series resistance, 66–67 Serotonin, 14, 16 in blood flow regulation, 94 glucocorticoids and, 239 Sertoli cells, 251, 258Q, 261E Serum anion gap, 173–174, 176 Set-point temperature, 56 Sex chromosomes, 249 Sexual differentiation, 249–250, 250 SGLT 1 (Na⫹-glucose cotransporter 1), 210 Shivering, 55, 59Q, 62E Short-term memory, 54 Shunt(s) left-to-right, 130–131, 274Q, 285E left-to-right ventricular, 101Q, 108E physiologic, 122 right-to-left, 130, 136Q, 138Q, 140E, 142E SIADH (see Syndrome of inappropriate antidiuretic hormone [SIADH]) Signal peptides, 222 Simple cells, of visual cortex, 42 Simple diffusion, 2–3, 2t, 25Q, 29E across capillary wall, 90 Single-unit smooth muscle, 21 Sinoatrial (SA) node action potentials of, 71, 71–72 pacemaker potential in, 103Q, 110E Sinusoids, 90 60-40-20 rule, 144 Size principle, 47 Skeletal muscle, 16–20 comparison of, 22t excitation–contraction coupling in, 18, 18–19, 19 temporal sequence of, 25Q–26Q, 29E Ca2⫹ binding in, 266Q, 277E–278E exercise effect on, 97 length–tension and force–velocity relationships in, 19–20, 20

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310

Index

Skeletal muscle (Continued) regulation of circulation to, 92t, 94–95 relaxation of, 19 structure of, 16–18, 17 Skin, regulation of circulation to, 92t, 95, 104Q, 111E Sleep, 54 Sleep–wake cycles, 54 Slow pain, 39 Slow waves, 54 gastrointestinal, 195, 195–196, 197, 217Q, 220E Slowly adapting receptors, 37 Small intestinal motility, 197–198, 217Q, 220E Small intestine, lipid digestion in, 212 Smooth muscle, 20–22, 21, 22t comparison with, 22t excitation–contraction coupling in, 21, 21–22, 23Q, 27E, 266Q, 277E–278E types of, 20–21 Sodium (see Na⫹) Sodium chloride (see NaCl) Solitary nucleus, in taste, 47 Solitary tract, in taste, 47 Somatomedins, 229, 229, 258Q, 262E Somatosensory cortex, 38 Somatosensory system, 38–39, 38t Somatostatin, 194, 223t, 245 and gastric acid secretion, 204, 205 and gastrin secretion, 193, 204, 205 and growth hormone secretion, 229, 229, 274Q, 286E and insulin secretion, 271Q, 282E Somatostatin analogs, 230 Somatotropin, 228, 229 Somatotropin release-inhibiting hormone (SRIF), 223t, 229 (see also Somatostatin) Sound encoding of, 44 frequency of, 43, 44 intensity, 43 Sound waves, 43 Spatial summation, 14, 50 Spermatogenesis, 251 Sphincter of Oddi, 208, 209 Spinal cord transection, effects of, 51, 59Q, 63E Spinal organization of motor systems, 50 Spinal shock, 51, 59Q, 63E Spinocerebellum, 51 Spiral ganglion, 43, 44 Spirometry, 113, 136Q, 140E Spironolactone, 162, 180Q, 185E, 268Q, 280E, 284E Splay, in glucose titration curve, 154 Sprue, tropical, 212 SR (sarcoplasmic reticulum), 16, 17, 18 myocardial, 75 SREs (steroid-responsive elements), 227, 227 SRIF (somatotropin release-inhibiting hormone), 223t, 229 (see also Somatostatin) ST segment, 69, 70, 108E, 1014Q Standing, cardiovascular responses to, 95–96, 95t, 96, 100Q, 107E Starling equation, 90, 90–91, 108E, 151 Starling forces and glomerular filtration rate, 150–151, 151, 152t in peritubular capillary blood, 157 Steady-state point, for cardiovascular system, 79, 80

Steatorrhea, 212, 216Q, 219E Stercobilin, 214, 215 Stereocilia, 45, 45 Stereospecificity, of carrier-mediated transport, 3 Steroid(s) 18-carbon, 237 19-carbon, 237 21-carbon, 236, 237 Steroid hormone(s) mechanisms of action, 224t, 227, 227 regulation of secretion, 238 synthesis of, 222, 269Q, 271Q, 280E, 282E Steroid-responsive elements (SREs), 227, 227 Stimulus, 36 Stomach lipid digestion in, 212 receptive relaxation of, 197, 216Q, 219E structure of, 197 Streptococcus pyogenes, fever due to, 267Q, 279E Stress, glucocorticoid response to, 239 Stretch reflex, 49, 49–50, 49t, 58Q, 59Q, 61E, 63E Striatum, 52, 53 lesions of, 53 Stroke volume afterload and, 78 in baroreceptor reflex, 87 defined, 82 end-diastolic volume and, 77, 77 exercise and, 273Q, 284E extrasystolic beat and, 100Q, 107E gravitational forces and, 95 preload and, 78 and pulse pressure, 68 Stroke work, 82 Sublingual glands, 200 Submandibular glands, 200 Submucosal plexus, of GI tract, 190, 191, 191 Substance P, 39 Substantia nigra, 52, 53 lesions of, 53 Subthalamic nuclei, 52, 53 lesions of, 53 Sucrase, 209, 210 Sucrose, digestion and absorption of, 217Q, 220E Sulfonylurea drugs, 244 Sulfuric acid, 169 Summation spatial, 14 at synapses, 14 temporal, 14 Supplementary motor cortex, 53 Suprachiasmatic nucleus, 54 Surface tension, of alveoli, 117–118 Surfactant, 118, 118 Surround, of receptive field, 54 Swallowing, 196 Sweat glands, 54 effect of the autonomic nervous system on, 35t in heat loss, 55 Sweating, water shifts between compartments due to, 147–148, 147t Sympathectomy, orthostatic hypotension after, 101Q, 108E Sympathetic effects, on heart rate and conduction velocity, 74 Sympathetic ganglia, 31

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Index Sympathetic innervation and blood flow to skeletal muscle, 94–95 to skin, 95 of vascular smooth muscle, 93 Sympathetic nervous system of GI tract, 191 in heat generation, 55 in heat loss, 55 organization of, 31, 32, 32t, 57Q, 61E and renal blood flow, 149 Sympathetic stimulation and airway resistance, 119 and myocardial contractility, 76 of saliva, 201, 202 Symport, 2t, 4, 4 Synapses input to, 14 many-to-one, 14 one-to-one, 14 summation at, 14 Synaptic cleft, 13 Synaptic transmission, 14–16, 15 Synaptic vesicles, 12 Syndrome of inappropriate antidiuretic hormone (SIADH), 270Q, 281E urine production in, 168, 168t vs. water deprivation, 182Q, 187E water shifts between compartments due to, 147t, 148 Systole, 68 atrial, 270Q, 281E Systolic pressure, 68, 68, 100Q, 107E Systolic pressure curve, 78 T T (transverse) tubules, 16, 17, 18 depolarization of, 18 myocardial, 75 T wave, 69, 70 T3 (triiodothyronine) actions of, 223t, 234–235 regulation of secretion of, 234, 234 reverse, 234 synthesis of, 232–233, 233, 234, 286E T4 (L-thyroxine) actions of, 223t, 234–235 regulation of secretion of, 234, 234 synthesis of, 232–233, 233, 234, 275Q, 286E Taste, 46–47, 59Q, 63E Taste buds, 46 Taste chemicals, 47 Taste pathways, 46–47 Taste receptor cells, 46 Taste transduction, 47 TBG (thyroxine-binding globulin), 233 TBW (total body water), 144, 145t measuring volume of, 144, 145t, 146 Tectorial membrane, 43, 44 Tectospinal tract, 51 Temperature, body core, 56 and hemoglobin–O2 dissociation curve, 126, 126 hypothalamic set point for, 56 Temperature regulation, 55–56 and blood flow to skin, 95 Temperature sensors, 56

311

Temporal summation, 14, 50 Terminal cisternae, 17, 18 Testes, regulation of, 251, 252 Testosterone actions of, 223t, 251, 252 conversion to dihydrotestosterone, 271Q, 282E and male phenotype, 250, 250 synthesis of, 237, 250, 251, 260Q, 264E, 268Q, 279E Tetanus, 19, 23Q, 27E Tetralogy of Fallot, 130 TG (thyroglobulin), 232, 233, 233 Thalamus, in somatosensory system, 38 Theca cells, 253 Thiazide diuretics and Ca2⫹ reabsorption, 163, 182Q, 187E contraindications to, 266Q, 277E for idiopathic hypercalciuria, 163 and K⫹ secretion, 162 major effects of, 177t mechanism of action of, 177t, 270Q, 281E site of action of, 158, 177t Thick ascending limb and Ca2⫹ reabsorption, 163 in K⫹ reabsorption, 158, 160 and Mg2⫹ reabsorption, 163 Na⫹ reabsorption in, 156, 156 in urine production, 164–166, 167 Thick filaments, 16–17, 17 Thin filaments, 17, 17–18 Thiocyanate, 232 Third-order neurons, 37 Threshold, 10 Threshold, defined, 153 Thromboxane A2, in blood flow regulation, 94 Thyroglobulin (TG), 232, 233, 233 Thyroid deiodinase, 233 Thyroid gland pathophysiology of, 236t physiology of, 232–235, 233, 234 Thyroid hormone in heat generation, 55 Thyroid hormones actions of, 234–235 mechanism of actions of, 227, 257Q–258Q, 261E regulation of secretion of, 234, 234 synthesis of, 232–233, 233, 234 Thyroid-stimulating hormone (TSH) actions of, 223t origin of, 223t, 258Q, 261E in regulation of secretion of thyroid hormone, 234, 234 structure of, 228 in synthesis of thyroid hormones, 232, 233 Thyroid-stimulating immunoglobulins, 234 Thyrotropin-releasing hormone (TRH) actions of, 223t and prolactin, 230, 230 in regulation of thyroid hormone secretion, 234, 234 L-thyroxine (T4) actions of, 223t, 234–235 regulation of secretion of, 234, 234 synthesis of, 232–233, 233, 234, 275Q, 286E Thyroxine-binding globulin (TBG), 233 Tidal volume (TV), 113, 114, 138Q, 141E Tight junctions, 1, 213

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312

Index

Titratable acid, 169 H⫹ excretion as, 172, 172 Titration curves, 170, 171 glucose, 153, 153–154 TLC (Total lung capacity), 115 Tm (transport maximum), 3 Tm (transport maximum) curve for reabsorbed substance, 153, 153–154 for secreted substance, 154, 154 Tonic contractions, in gastrointestinal motility, 195 Tonic receptors, 37 Tonotopic representation, 44 Total body water (TBW), 144, 145t measuring volume of, 144, 145t, 146 Total lung capacity (TLC), 115 Total peripheral resistance (TPR) ␣1 receptors and, 269Q, 280E arteriolar pressure and, 107E and cardiac output and venous return curve, 81, 82 exercise effect on, 97, 102Q, 104Q, 109E, 111E Total tension, 19, 20 TPR (see Total peripheral resistance [TPR]) Transducin, 41, 42 Transferrin, 214 Transport across cell membranes, 2–5, 2t, 4, 5 active primary, 2t, 3–4, 26Q, 30E secondary, 2t, 4, 4–5, 5, 26Q, 30E primary, 274Q, 285E carrier-mediated, 3 coupled, 4 Transport maximum (Tm), 3 Transport maximum (Tm) curve for reabsorbed substance, 153, 153–154 for secreted substance, 154, 154 Transverse (T) tubules, 16, 17, 18 depolarization of, 18 Trauma, and blood flow to skin, 95 Trehalase, 209, 210 Tremor, intention, 52 TRH (thyrotropin-releasing hormone) actions of, 223t and prolactin, 230, 230 in regulation of thyroid hormone secretion, 234, 234 Tricuspid valve, closure of, 83 Triiodothyronine (T3) actions of, 223t, 234–235 regulation of secretion of, 234, 234 reverse, 234 synthesis of, 232–233, 233, 234, 286E Tripeptides, 211, 212 Tritiated water, as marker for TBW, 145 Tropical sprue, 212 Tropomyosin, 17 Troponin, 17 Troponin C, Ca2⫹-binding to, 17 Trypsin, 211 Trypsinogen, 211 Tryptophan, and gastrin secretion, 193 TSH (see Thyroid-stimulating hormone [TSH]) Tubular fluid (TF), 155 alanine in, 184Q, 189E creatinine concentration in, 272Q, 283E

glomerular filtrate in, 272Q, 283E glucose in, 184Q, 189E HCO3– in, 272Q, 283E inulin in, 184Q, 189E K⫹ in, 272Q, 283E paraaminohippuric acid in, 272Q, 283E Para-aminohippuric acid in, 184Q, 189E plasma-like, 272Q, 283E with water deprivation, 272Q–273Q, 283E Tubular fluid/plasma (TF/P) ratio, 155–156 Tubuloglomerular feedback, 149 TV (Tidal volume), 113, 114, 138Q, 141E Twitch tension, 19 Tympanic membrane, 43 Type II alveolar cells, 118 U UDP (uridine diphosphate) glucuronyl transferase, 214, 215 Ulcer(s) duodenal, 206, 217Q, 220E gastric, 205 peptic, 205–206, 218Q, 221E Ultrafiltration pressure, net, 150, 151 Undershoot, of action potential, 11 Unitary smooth muscle, 21 Unmyelinated axon, 11, 12 Upper esophageal sphincter, 196 Up-regulation, of hormone receptors, 224 Upstroke, of action potential, 10–11, 23Q, 25Q, 27E, 28E Urea glucagon and, 243 hypotonic, 24Q, 28E renal regulation of, 162–163 Urea recycling, in urine production, 164 Uridine diphosphate (UDP) glucuronyl transferase, 214, 215 Urinary buffers, 169 Urine concentrated (hyperosmotic), 163–166, 165 dilute (hyposmotic), 166, 166–167, 180Q, 185E isosthenuric, 168 osmolarity of, 182Q, 187E Urine pH, 172 acidic, 155 alkaline, 155 minimum, 172 Urobilin, 214, 215 Urobilinogen, 214, 215 Utricle, 44 V V (Alveolar ventilation), 114, 121, 131, 142E V1 agonists, 273Q, 283E–284 V1 receptors, 89 V2 receptors, 89 Vagal stimulation, of gastric H⫹ secretion, 203–204 Vagotomy and H⫹ secretion, 204 and saliva, 266Q, 277E Vagovagal reflexes, 191, 208 Vagus nerve, 191 Valsalva maneuver, 198 Vanillylmandelic acid (VMA), 15, 31 van’t Hoff’s law, 6 Vasa recta, in urine production, 164

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Index Vascular capacitance and pulse pressure, 273Q, 284E Vascular resistance, 66–67 blood vessel radius and, 66, 100Q, 107E, 268Q, 279E Vascular smooth muscle, 21 effect of autonomic nervous system on, 35t sympathetic innervation of, 93 Vasculature, components of, 64–65 Vasoactive intestinal peptide (VIP), 194–195 in esophageal motility, 196 and GI smooth muscle relaxation, 216Q, 219E Vasoconstriction, 93–95 antidiuretic hormone in, 267Q, 274Q, 278E, 285E in baroreceptor reflex, 87 in hemorrhage, 99 hypoxic, 130, 136Q, 140E, 274Q, 285E pulmonary, in high altitudes, 135 of renal arterioles, 149 Vasodilation, 93–95 of renal arterioles, 149 Vasodilator metabolites, 93 exercise and, 97 Vasomotor center in baroreceptor refle, 86 chemoreceptors in, 89 Vasopressin, and arterial blood pressure, 89 VC (Vital capacity), 114, 115 measurement of, 136Q, 140E Veins, 65 Venoconstriction in baroreceptor reflex, 87 Venous blood, pH of, 139Q, 143E Venous compliance and mean systemic pressure, 79, 80 and venous return curve, 81 Venous constriction, 94 Venous pooling, 95, 100Q, 107E Venous pressure, 69 and edema, 102Q, 109E Venous return and cardiac output, 77 diarrhea and, 104Q, 111E exercise and, 96 Venous return curve, 79–81, 80 Ventilation alveolar, 114, 121, 131, 142E minute, 114 positive pressure, pulmonary blood flow of, 130 Ventilation/perfusion (V/Q) defects, 131, 131–132, 133t Ventilation/perfusion (V/Q) ratio with airway obstruction, 131–132 changes in, 131–132 defined, 131 in different parts of lung, 131, 131, 270Q, 281E during excercise, 135 in pulmonary embolism, 132, 137Q, 141E Ventral respiratory group, 133 Ventricles, length–tension relationship in, 76–77, 77 Ventricular action potential, 70, 70–72, 71, 103Q, 110E Ventricular ejection, 78 rapid, 85 reduced, 85

313

Ventricular filling, 72, 78 heart rate and, 268Q, 279E rapid, 85 reduced, 85 Ventricular pressure–volume loop, 77, 77–79, 78 Ventricular shunt, left-to-right, 101Q, 108E Ventricular volume, 84, 101Q, 107E Venules, 65 Vestibular organ, 44–45 Vestibular system, 44–46, 45 Vestibular transduction, 45, 45 Vestibular–ocular reflexes, 45–46 Vestibule, of inner ear, 43 Vestibulocerebellum, 51 Vestibulospinal tract, lateral, 51 Vibrio cholerae, 213 VIP (vasoactive intestinal peptide), 194–195 in esophageal motility, 196 and GI smooth muscle relaxation, 216Q, 219E Vision, 39–42 layers of retina in, 39, 40, 40t optic pathways and lesions in, 40, 41 optics in, 39 photoreception in rods in, 40–41, 42 receptive visual fields in, 41–42 Visual cortex, receptive fields of, 42 Vital capacity (VC) measurement of, 136Q, 140E Vitamin(s), absorption of, 210t, 214 Vitamin A, in photoreception, 40, 41 Vitamin B12, absorption of, 210t, 214, 269Q, 280E Vitamin D, 248–249 actions of, 246t, 249 in calcium metabolism, 246 metabolism of, 246t, 249, 249 VMA (3-methoxy- 4-hydroxymandelic acid), 31 VMA (vanillylmandelic acid), 15 Volatile acid, 168–169 Voltage-gated channels, 7 Volume contraction alkalosis, 174t, 175 due to diarrhea, 179 hyperosmotic, 147–148, 147t in hypoaldosteronism, 178 hyposmotic, 147t, 148 isosmotic, 147, 147t due to vomiting, 178 Volume expansion hyperosmotic, 147, 147t hyposmotic, 147t, 148 isosmotic, 146, 146, 147t Volume of distribution, 145 Vomiting, 178, 199 and gastric secretion, 202–203 metabolic alkalosis due to, 174, 178, 179, 183Q, 189E, 271Q, 282E V/Q (see Ventilation/perfusion [V/Q]) W Water (H2O) absorption of, 213 distribution of, 144, 145, 145t secretion of, 213 shifts between compartments of, 146, 146–148, 147t total body, 144, 145t measuring volume of, 144, 145t, 146 tritiated, 145

98761_Index 11/05/10 3:34 PM Page 314

314

Index

Water deprivation, 164, 168t and free-water clearance, 168, 265Q–266Q, 276E–277E and H2O reabsorption, 181Q, 186E and serum osmolarity, 273Q, 284E–285E and TF/P osmolarity, 184Q, 189E tubular fluid with, 272Q–273Q, 283E Water intake, response to, 165 Water-soluble substances, and cell membrane, 1 Weak acids, 155 Weak bases, 155 Wernicke’s area, 54

Wheal, 95 Wolff–Chaikoff effect, 233 Wolffian ducts, 250 Z Z line, 16, 17 Zollinger–Ellison syndrome, 193, 206, 218Q, 221E Zona fasciculata, 235, 236, 237 Zona glomerulosa, 235, 236, 237, 258Q, 262E Zona reticularis, 236, 236, 237 Zonula occludens, 1

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